AidsInfo Drugs RSS Feed<![CDATA[AMD070]]>[#] [#] [#]]]>[#] [#] [#]]]>[#] [#] [#]]]>[#]]]>[#] Dosages of 100 mg and 200 mg AMD070 twice daily have been studied for up to 10 days in Phase II trials. [#]]]>[#]]]>[#]

AMD070 has not yet been fully evaluated in human trials. A small Phase I safety study of AMD070 in HIV uninfected male volunteers evaluated the safety, pharmacokinetic profile, and bioavailability of single and multiple doses of AMD070. Thirty subjects participated in this study. Single doses of 50, 100, 200, and 400 mg and multiple doses of 100, 200, and 400 mg twice daily (five doses, with pharmacokinetic sampling performed following the last dose) were examined. Dose-dependent increases in the peak plasma concentration (Cmax) and the median area under the concentration-time curve (AUC) were observed following both single and multiple doses. Evidence of AMD070 accumulation was noted with repeated administration. [#]

AMD 070 is readily absorbed in humans after oral administration. [#] When studied in HIV infected patients with CXCR4-tropic virus, AMD070 displayed a greater-than-proportional increase in exposure across 100 and 200 mg twice-daily dosage groups, consisting of eight and two participants, respectively. Mean Cmax were 346.5 ng/ml and 1,271.2 ng/ml in the 100 and 200 mg groups, respectively. Mean AUC were 1,123.5 mg(h)/ml and 6,471.8 ng(h)/ml in the same groups, respectively. The half-life of 200 mg AMD070 twice daily was 5.5 h. AMD070 accumulates with repeat administration, although minimum plasma concentrations in this study did not achieve steady-state levels after 10 days of administration. [#] AMD070 Cmax, AUC, and half-life are increased when administered concurrent with steady-state levels of ritonavir as a pharmacokinetic booster. [#]

Because no information concerning the reproductive toxicity of AMD070 is currently available, AMD070 is not being tested in women at this time, and male volunteers in AMD070 clinical trials are advised to avoid participating in conception activities during AMD070 administration and for 2 weeks after stopping the drug. [#] AMD070 is not mutagenic in vitro; however, CXCR4 may play a role in hematopoiesis in utero. [#]

AMD070 is 84% to 97% protein bound at pharmacologically active concentrations; however, protein binding does not appear to have a significant effect in vitro. Limited information is available concerning the metabolism of AMD070. AMD070 represents the major circulating form of the drug in plasma; several putative metabolites have been noted in plasma samples from in vivo preclinical studies. [#] Based on preliminary laboratory studies, AMD070 is a substrate for cytochrome P450 (CYP) 3A4 but has a low potential for induction. AMD070 moderately inhibits CYP2D6 and exhibits time-dependent inhibition of CYP3A4. [#]

Median total body clearance of AMD070 is 216 l/hr. AMD070 is eliminated in at least a biexponential manner, and the median terminal half-life is 16 hours. [#] [#]

AMD070 appears to share nearly overlapping binding sites with a previously investigated CXCR4 inhibitor, AMD3100. However, the amino acid residue D97 on the CXCR4 receptor interacts specifically with AMD070 alone. Decreased AMD070 binding potency of more than 100-fold has been associated with W94A, D97N, D171N, and E288A mutations. Binding potency decreases of 10- to 50-fold have been observed with 445A and D262N mutations. [#]

A small safety trial of AMD070 monotherapy for 10 days compared 100 and 200 mg twice-daily dosages in eight and two participants, respectively. All patients had CXCR4- or mixed-tropic virus and were treatment-naive or at least free from antiretroviral treatment for 14 days. By Day 5, two of four responding participants experienced a tropism switch to CCR5-tropic virus, and one more participant experienced a tropism switch at Day 10. [#]]]>
[#] the adverse events reported for AMD3100 may be similar to those for AMD070. In a study of 40 HIV infected people, AMD3100 was administered intravenously via a 10-day continuous infusion up to 160 mcg/kg/hour. The most common subjective complaints from study participants, regardless of whether they were attributed to study drug, included diarrhea (48%), flatulence (43%), headache (40%), nausea (35%), abdominal pain (33%), abdominal distension (25%), tachycardia (25%), dizziness (25%) and paresthesias (23%). Vital sign abnormalities, including hypertension (67%), hypotension (25%), and tachycardia (47%), were observed transiently in many participants, although there were no dose-related trends. Several-fold increases in white blood cells, CD4 counts, and lymphocytes were seen in all participants but were not of clinical concern. [#]

In a small, Phase I safety study of AMD070 in HIV uninfected volunteers, the drug was generally well tolerated; 3 of 12 participants complained of a transient, mild-to-moderate headache after taking a single dose of AMD070 on an empty stomach. [#] No serious adverse events were reported, and adverse events were generally mild (mainly Grade 1 or 2). The most common adverse effects were pain, gastrointestinal disturbances, and Grade 1 tachycardia; other reported events included lightheadedness, palpitations, insomnia, shaky and unsteady hands, a flushed feeling, seasonal allergies, a buzzing sensation, and heartburn. [#]

Short-term administration has a potential for acute gastrointestinal toxicity, characterized by vomiting and diarrhea that usually occurs within 1 to 2 hours of administration. These effects are expected to be transient. Bone marrow hypocellularity has been observed at the highest dose levels; reversibility of this effect has not been demonstrated. Lymphoid atrophy has been observed in the thymus, lymph nodes, and spleen. Heart rate elevations and blood pressure changes have also been noted. [#]

Dosages of 200 mg AMD070 twice daily for 10 days have been well tolerated in HIV infected patients. No Grade 3 or greater toxicities were observed during and up to 7 days after treatment. [#] In two small studies of 100 or 200 mg AMD070 twice daily, given alone or coadministered with ritonavir, no serious, drug-related adverse events or laboratory abnormalities were reported. The most common adverse effects experienced in HIV infected patients taking 10-day monotherapy were mild gastrointestinal symptoms and headache. [#] [#]]]>
[#] In a small study of HIV uninfected volunteers, absorption of AMD070 did not appear affected by food. [#]

In vitro studies using five different CD4 cell lines, CXCR-transfected cell lines, and peripheral blood mononuclear cells indicated that AMD070 had additive or synergistic antiviral activity when combined with other known HIV inhibitors, including fusion inhibitors (enfuvirtide), nucleoside reverse transcriptase inhibitors (zidovudine and tenofovir), and protease inhibitors (amprenavir). [#]

Because AMD070 is a substrate of CYP3A4 and p-glycoprotein, it will likely be administered with a ritonavir booster. The hypothesis of favorably altered pharmacokinetics of AMD070 was tested in healthy volunteers, who received single doses of 200 mg AMD070 on Days 1, 3, and 17, and ritonavir 100 mg every 12 hours on Days 3 through 18. Ritonavir boosting at steady-state decreased the time to maximum concentration of AMD070 by 25%, increased the Cmax of AMD070 by 47%, increased the AUC of AMD979 by 24%, and increased the half-life of AMD070 by 16%. [#]

As a substrate of CYP3A4, AMD070 has low induction potential and time-dependent inhibition activity. In addition, AMD070 is a moderate inhibitor of CYP2D6. When a single dose of AMD070 was tested in combination with midazolam, a CYP3A4 substrate, and dextromethorphan, a CYP2D6 substrate, statistically significant increases in AUC were observed for both midazolam and dextromethorphan. A statistically significant increase in Cmax of dextromethorphan was observed as well. The clinical effects and dose-altering requirements of these increases are unknown. [#]]]>
[#] ]]>[#]]]>[#]]]> Stone ND, Dunaway SB, Flexner CW, Tierney C, Calandra GB, Becker S, Cao YJ, Wiggins IP, Conley J, Macfarland RT, Park JG, Lalama C, Snyder S, Kallungal B, Klingman KL, Hendrix CW. Multiple Dose Escalation Study of the Safety, Pharmacokinetics, and Biologic Activity of Oral AMD070, a selective CXCR4 Receptor Inhibitor, in Human Subjects (ACTG A5191). Antimicrob Agents Chemother. 2007 Apr 23; [Epub ahead of print]
Boffito M, Moyle G, Wong R, Chee P, MacFarland R, Calandra G, Bridger G, and Becker S. Pharmacokinetics of AMD11070, a CXCR4 Antagonist, in HIV-infected Patients Carrying X4-tropic Virus. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 571, 2007.
Cao Y, Flexner C, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J, Radebaugh C, Becker S, Hendrix C, and the A5191 Study Team. Ritonavir Increases Concentrations of the CXCR4 Antagonist AMD070 in Healthy Volunteers. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 570, 2007.
Schols D, Claes S, Hatse S, Princen K, Vermeire K, De Clercq E, Skerlj R, Bridger G, and Calandra G. Anti-HIV activity profile of AMD070, an orally bioavailable CXCR4 antagonist. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, Paper 563, 2003.]]>
Cambridge, MA 02142
Phone: 617-252-7500
Fax: 800-737-3642]]>
<![CDATA[PRO 140]]>[#] ]]>[#] ]]>[#] To date, two Phase I studies studies of the safety and pharmacokinetics (PK) of PRO 140 given intravenously have been completed, one in HIV uninfected males and another in HIV-1 infected individuals of both sexes. Two Phase II studies of the safety and PK of PRO 140 given intravenously and subcutaneously are ongoing, in the interim yielding positive results. [#] [#] [#] PRO 140 was granted fast-track status by the FDA in February 2006. [#] ]]>[#] [#] ]]>[#] [#] [#]

Subcutaneous injections of 324 mg of PRO 140 have been administered to HIV infected individuals in one clinical trial. [#] ]]>
[#] PRO 140 inhibits entry of HIV into cells by preventing virus-cell binding at a distinct site on the CCR5 coreceptor without interfering with the natural activity of CCR5. It binds an extracellular (not a transmembrane) site, inhibiting HIV via a competitive (rather allosteric) mechanism. [#] PRO 140 exhibits dose-dependent binding to CCR5-expressing cells, significantly coating and protecting such cells for up to 60 days. [#] PRO 140 broadly and potently inhibits wild-type and drug-resistant, R5-tropic HIV in vitro. It is also synergistic with small-molecule CCR5 antagonists. [#] This synergistic effect seen when combining PRO 140 with other investigational CCR5 inhibitors suggests that PRO 140 may represent a distinct subclass of CCR5 inhibitors. [#]

A Phase I, randomized, double-blind, placebo-controlled study was conducted to examine the safety, PK, and pharmacodynamics of single-dose PRO 140 in 20 healthy males. Participants received intravenous PRO 140 doses of 0.1, 0.5, 2, and 5 mg/kg in sequential, dose-rising cohorts of 5 (4 active, 1 placebo) each and were evaluated for 60 days post-treatment. Serum concentrations of PRO 140 increased proportionally with dose; the serum half-life was approximately 2 weeks. Cellular CCR5 receptors remained coated with PRO 140 for greater than 60 days at the 5 mg/kg dose. No anti-PRO 140 antibodies were observed in preliminary bioanalytical testing. [#] [#]

In another Phase I, randomized, double-blind, placebo-controlled study, the safety, tolerability, antiviral activity, and PK of single-dose PRO 140 administered intravenously were studied in 39 HIV infected participants. Doses of PRO 140 of 0.5, 2, or 5 mg/kg were administered. A 10-fold (90%) reduction in viral load from baseline was observed as early as Day 5; the average viral load reduction by Day 10 was approximately 99%. All participants who received 5 mg/kg PRO 140 experienced at least a 10-fold reduction in viral load from baseline. The 2.0 mg/kg dose reduced viral load by an average of 90%; the 0.5 mg/kg dose reduced viral load by an average of 50%. A 29% (p=0.055) average increase in CD4 cells by Day 8 was also observed, suggesting a trend of increased CD4 count with PRO 140 use. Potent, rapid, prolonged, dose-dependent significant antiviral activity was observed across all dose groups. PK studies indicated that peak and total exposure increased proportionally or better with dose. Peak levels of PRO 140 were achieved within 3 to 60 minutes, and the terminal half-life of PRO 140 was determined to be about 4 days. Low titer anti-PRO 140 antibodies developed in one participant who received the 5.0 mg/kg dose; no obvious effect on PK or antiviral response could be discerned. Ex vivo fluorescently-labeled lymphocytes analyzed by flow cytometry indicated obvious coating of CCR5 lymphocytes by PRO 140, with a duration of coating of 1 to 2 weeks consistent with the compound's antiviral effects. [#]

In vitro antiviral activity of PR0 140 was independent of HIV-1 subtype and resistance to existing antiretroviral treatment classes. [#] PRO 140 exhibited potent, broad-spectrum activity in laboratory studies of more than 40 genetically diverse HIV strains. The strains failed to develop resistance to PRO 140, even after 40 weeks of continued exposure in vitro. [#] ]]>
[#] [#] No obvious, infusion-related, or dose-limiting toxicities, drug-related adverse effects [#] [#] , or electrocardiogram changes occurred with single doses ranging from 0.1 to 5 mg/kg. [#] ]]>[#] and maraviroc [#] and with investigational small-molecule CCR5 antagonists, such as SCH-D (vicriviroc). [#] [#] ]]>[#] ]]>Biswas P, Tambussi G, Lazzarin. A. Access denied? The status of co-receptor inhibition to counter HIV entry. Expert Opin Pharmacother. 2007 May;8(7):923-33.
Murga JD, Franti M, Pevear DC, Maddon PJ, Olson WC. Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob Agents Chemother - 2006 Oct;50(10):3289-96.
Ketas TJ, DiPippo VA, Lam E, Maddon PJ, Olson WC. PRO 140, a Humanized CCR5 Monoclonal Antibody, is Active Against Genotypically Diverse and Enfuvirtide-Resistant Strains of HIV-1. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, Sydney, Australia, Abstract WEPEA093, 2007.
Saag MS, Jacobson JM, Thompson M, Fischl M, Liporace R, Reichman RC, Redfield RR, Fichtenbaum CJ, Zingman BS, Patel MC, D'Ambrosio P, Michael M, Kroger H, Ly H, Rotshteyn Y, Stavola JJ, Maddon PG, Kremer AB, Olson WC. Antiviral Effects and Tolerability of the CCR5 Monoclonal Antibody PRO 140: A Proof of Concept Study in HIV-Infected Individuals. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, Sydney, Australia, Abstract WESS201, 2007.]]>
Tarrytown, NY 10591]]>
<![CDATA[TNX-355]]>[#] [#] TNX-355 is currently being developed by TaiMed Biologics, through licensing with Genetech, Inc. [#] [#] ]]>[#] [#] TNX-355 is currently being developed by TaiMed Biologics, through licensing with Genetech, Inc. [#] [#] ]]>[#] [#] TNX-355 was granted fast-track status by the FDA in October 2003. [#] Additional Phase II, dose-finding studies had been initiated by Tanox Inc; however, the drug is now licensed to TaiMed Biologics through Genetic Inc, and no new studies have been initiated yet. [#] [#] ]]>[#] ]]>[#] In another study TNX-355 is also being administered intravenously but at a dosage of 800 mg every 2 weeks or at 2000 mg every 4 weeks. [#] ]]>[#]

In vitro laboratory studies of HIV-1 subtype B isolates from 82 triple-class-experienced patients evaluated TNX-355 susceptibility based on viral tropism. Of the 82 isolates, 49 were M-tropic, two were T-tropic, and 27 were dual- or mixed-tropic. All isolates were similarly susceptible to TNX-355, and degree of efficacy did not appear associated with tropism. [#]

A Phase Ia study evaluated single 0.3 to 25 mg/kg doses of TNX-355; these doses reduced viral load from baseline by 50% to 90%. This effect was transient, with most levels returning to baseline by Day 28. Significant viral load reductions were observed with the 10 and 25 mg/kg doses and were sustained for 2 to 3 weeks. [#]

In a Phase Ib study, 23% of patients had reduced viral loads by greater than 95%, and 64% had reduced loads by greater than 90%. However, these reductions were also transient, implying that monotherapy may cause quick development of resistance. [#]

A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of TNX-355 was conducted with 22 HIV-1-infected patients. Treatment with TNX-355 demonstrated significant reductions in HIV-1 RNA levels in 20 of 22 patients. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Emerging resistance to TNX-355 was shown. TNX-355 did not have immunogenic activity, and no serious drug-related adverse effects occurred. TNX-355 administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. [#]

An ongoing Phase II, multicenter, randomized, double-blind, placebo-controlled trial is evaluating TNX-355 efficacy and safety in 82 triple-class-experienced patients also on optimized background therapy. The trial is comparing HIV-infected patients who have failed or are failing highly active antiretroviral therapy (HAART) assigned to one of three arms: TNX-355 10 mg/kg once weekly for nine doses followed by 10 mg/kg every other week; TNX-355 15 mg/kg every other week; or placebo. The study is evaluating virologic failure rates and viral load reduction between the two doses and between each dose and placebo. Enrolled patients must have a viral load of 10,000 copies/ml or greater, a CD4 count greater than 50 cells/ml, and triple-class experience with HAART. [#] At the Week 24 interim analysis, viral load decreased by -nearly 10-fold in the 15 mg/kg arm, by 15-fold in the 10 mg/kg arm, and by nearly twofold in the placebo arm. Both treatment arm reductions were statistically greater than the placebo reduction. [#]

Susceptibility of enfuvirtide-resistant viral envelopes to TNX-355 was studied in vitro using G36D, V38A, and N43D substitutions. Envelopes exhibited 11- to 32-fold reduced susceptibility to enfuvirtide but less than twofold reduced susceptibility to TNX-355. No cross resistance to TNX-355 was observed. [#] ]]>
[#] [#] ]]>[#] This synergy, along with the differing mechanisms of action and resistance between these two entry inhibitors, supports a strategy of coadministration. [#] ]]>[#] 872357-57-8 [#] ]]>Dimitrov A. Ibalizumab, a CD4-specific mAb to inhibit HIV-1 infection. Curr Opin Investig Drugs. 2007 Aug;8(8):653-61.
Jacobson JM, Kuritzkes DR, Godofsky E, DeJesus E, Lewis S, Jackson J, Frazier K, Fagan EA, Shanahan WR. Phase 1b Study of the Anti-CD4 Monoclonal Antibody TNX-355 in HIV-1-infected Subjects: Safety and Antiretroviral Activity of Multiple Doses. Eleventh Conference on Retroviruses and Opportunistic Infections,San Francisco, CA, February 2004. Abstract 536.
TNX-355 With Optimized Background Therapy (OBT) in Treatment-Experienced Subjects With HIV-1. Available at: Accessed 05/05/09.
Zhang XQ, Sorensen M, Fung M, Schooley RT. Synergistic in vitro antiretroviral activity of a humanized monoclonal anti-CD4 antibody (TNX-355) and enfuvirtide (T-20). Antimicrob Agents Chemother. 2006 Jun;50(6):2231-3.
Jacobson JM, Kuritzkes DR, Godofsky E, DeJesus E, Larson JA, Weinheimer SP, Lewis ST. Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults. Antimicrob Agents Chemother. 2009 Feb;53(2):450-7. Epub 2008 Nov 17.
A Phase 2b, Randomized, Double-Blinded, 48-Week, Multicenter, Dose-Response Study of Ibalizumab Plus an Optimized Background Regimen in Treatment-Experienced Patients Infected With HIV-1. Available at: Accessed 06/04/09.]]>
Houston, TX 77025
Phone: 866-312-5200
Fax: 713-578-5002]]>
<![CDATA[Vicriviroc maleate]]>[#] [#] [#]]]>[#] [#] [#]]]>[#] [#]

Vicriviroc, a piperazine-based CCR5 antagonist, is a novel, orally active entry and fusion inhibitor that was previously in development for use in HIV infected patients who are resistant to enfuvirtide and other antiretrovirals. [#] [#] [#]]]>
[#]]]>[#]]]>[#] [#] [#]

The 5-mg dose was discontinued early in trials conducted in treatment-experienced patients. This dose was associated with poor efficacy, and eight patients receiving vicriviroc developed malignancies. [#] [#]

The manufacturer has studied vicriviroc 30 mg once daily in multiple phase III trials. [#]]]>

Vicriviroc is a small-molecule inhibitor that binds to the cell's CCR5 receptor. When the drug binds to the CCR5 receptor, the receptor's conformation changes. This prevents HIV's gp120 protein from binding to CCR5 and consequently prevents the virus from entering the cell. [#]

Vicriviroc has been safe and well tolerated in HIV infected, treatment-naive patients participating in vicriviroc Phase I trials receiving 10-, 25-, and 50-mg twice-daily dosages of the drug. At these doses, a nadir of HIV-1 viral load was observed after 10 to 14 days of dosing. [#] Phase I trial data in treatment-naive HIV patients suggest that vicriviroc's suppression of HIV viral load is dose dependent. Vicriviroc does not appear to induce cytochrome P450 (CYP) 3A4 and has an elimination half-life of approximately 24 hours. [#] Vicriviroc has excellent oral bioavailability, is rapidly absorbed, and has a large apparent volume of distribution. The rapid absorption and a half-life range of 28 to 33 hours both support once-daily dosing of vicriviroc. [#] [#] Minimum (trough) plasma concentrations, or trough concentrations (Cmin), of vicriviroc appear to predict virologic response, as evidenced in ACTG A5211, a Phase II study of vicriviroc 5, 10, or 15 mg given once daily in 86 HIV infected participants with CCR5-tropic virus. At 2 weeks, Cmins averaged 42.3 ng/ml with the 5-mg dose, 90.9 ng/ml with the 10-mg dose, and 121 ng/ml with the 15-mg dose. In participants with Cmins greater than or equal to 53.7 ng/ml, 70% had at least a 10-fold reduction in viral load levels compared with 44% of participants who had lower Cmins. [#]

In the Phase II ACTG A5211 trial, 118 treatment-experienced patients with CCR5-tropic HIV were randomized to receive vicriviroc 5, 10, or 15 mg once daily or placebo in addition to ritonavir-boosted, PI-containing regimens. Vicriviroc demonstrated potent and sustained viral suppression through 48 weeks of therapy. At Day 14 and at Week 24, the median viral load reductions from baseline were statistically greater in the 5-, 10- and 15-mg vicriviroc groups (approximately 85% and 97%, 90% and 99%, and 85% and 98%, respectively) than in the placebo group (slight increase and 50% reduction, respectively). At Week 48, patients in the 10- and 15-mg treatment groups achieved a median decrease in viral load of 99% and 96%, respectively, and a median CD4 count increase from baseline of 130 and 96 cells/mm3, respectively. More patients in the vicriviroc groups had undetectable virus at 48 weeks (HIV-1 viral load less than 50 copies/ml) compared with those in the placebo group (57/37% and 43/27% vs. 14/11%, respectively), and fewer patients in the vicriviroc groups experienced virologic failure compared to those in the placebo group (27 and 33% vs. 86%, respectively). [#] Among participants in the 10- and 15-mg treatment groups who had viral load levels less than 50 copies at Week 24, 70% retained that level through Week 48. Although all participants had CCR5-tropic virus at baseline screening, 12 participants (10%) had dual/mixed virus when the study regimen began. The time to virologic failure tended to be faster in people with dual/mixed virus when the study began than in those with R5-only virus. In addition, tropism switches from CCR5-tropic to CXCR4- or dual/mixed-tropic virus occurred in 7 (12%) of 60 participants taking vicriviroc 10 or 15 mg and in 8 participants taking vicriviroc 5 mg. Among 26 vicriviroc-treated people who had a virologic failure, 9 (35%) saw their virus change coreceptor preference from CCR5 to CXCR4 or dual/mixed tropism. After dual/mixed or X4-using virus emerged in people taking vicriviroc, viral loads and CD4 counts remained relatively stable through Week 48. [#] [#]

After completion of the expanded, 48-week ACTG A5211 trial, 39 HIV infected participants voluntarily continued taking vicriviroc 15 mg in combination with optimized background therapy (OBT). Two-year results of the open-label study showed long-lasting viral load reductions of more than 99% from prestudy levels. Sixty percent of participants maintained viral load levels less than 50 copies. In addition, CD4 levels after 2 years of vicriviroc treatment were approximately 84 cells/mm3 greater than prestudy levels. Two patients experienced viral load rebound, and 6 patients experienced a tropism switch from CCR5-tropic virus to either CXCR4- or dual/mixed-tropic virus. [#] [#] This study found that patients with dual/mixed-tropic virus had significantly lower CD4 counts than patients with CCR5-tropic virus only. This finding emphasizes the importance of evaluating coreceptor use in the clinical development of CCR5 and CXCR4 inhibitors. [#]

Another Phase II trial, VICTOR-E1, is ongoing to compare vicriviroc 20 and 30 mg with placebo in combination with a ritonavir-boosted, PI-containing antiretroviral regimen. [#] [#] VICTOR-E1 is a randomized, double-blind, placebo-controlled, dose-finding study in 116 antiretroviral-experienced participants with CCR5-tropic HIV-1. At Week 12, during a safety evaluation, CD4 levels were generally sustained or increased. Tropism changes from CCR5-tropic to dual/mixed-tropic virus were noted in six participants after screening but before drug administration began. Further, treatment-emergent tropism shifts generally did not result in reduced CD4 counts and were not associated with immune decline. [#] This trial also examined coreceptor usage and tropism-associated variables. Approximately 35% of screened participants had dual or mixed-tropic virus, 4% had CXCR4-tropic virus, and 45% had CCR5-tropic virus; the assay failed in the remaining 15%. Dual/mixed- or CXCR4-tropic virus at screening was associated with lower mean CD4 counts than CCR5-tropic virus; participants with CCR5-tropic virus experienced significantly greater CD4 counts compared with those with non-CCR5-tropic virus. In contrast, age, resistance mutations, gender, and baseline viral load levels had no correlation with coreceptor usage. [#] Efficacy of both vicriviroc 20 and 30 mg was examined at a Week 24 analysis, and viral load was reduced significantly in both groups compared with placebo. HIV RNA was reduced by -2.04 log in both treatment arms. However, undetectable HIV RNA levels (less than 50 copies/ml) were achieved in 64% of patients on vicriviroc 30 mg but in 58% of patients on vicriviroc 20 mg. [#] At a Week 48 analysis, vicriviroc 20 and 30 mg continued to display efficacy in reducing HIV RNA. Viral load was reduced to less than 50 copies/ml in 56% of patients on vicriviroc 30 mg and in 52% of patients on vicriviroc 20 mg. On the basis of the Week 24 and Week 48 efficacy at achieving undetectable virus, the manufacturer continued further study in Phase III trials with the 30-mg dose as the more efficacious option. [#]

Two large, Phase III trials of vicriviroc 30 mg once daily in combination with a ritonavir-boosted, PI- containing OBT were initiated in 2007 in treatment-experienced participants with multidrug-resistant HIV and with CCR5-tropic virus at baseline screening. VICTOR-E3 and -E4 evaluated the efficacy of the addition of vicriviroc to OBT compared with OBT alone. [#] [#] [#] Initial Phase III pooled study results found that vicriviroc did not meet the primary efficacy endpoint of superiority over OBT. Results showed that at week 48 of treatment, 64 and 62 percent of patients in the vicriviroc and placebo arms, respectively, had undetectable virus (HIV-1 RNA less than 50 copies/mL), the primary efficacy endpoint.  This difference did not reach statistical significance (p=0.6). Additional results found that 72 and 71 percent of patients in the vicriviroc and placebo arms, had HIV-1 RNA less than 400 copies/mL, respectively. The mean changes in CD4 counts were +137.8 and +128.6 cells/mm3, respectively. [#]
Mutation in V3 loop sites of HIV's env gene have occurred in some participants who experienced treatment failure in Phase II studies. None of these mutations developed in participants who received vicriviroc 15 mg. The V3 mutations arose at different loop sites in each case and did not correlate directly with reduced viral susceptibility to vicriviroc; thus, it is unlikely that these mutations explain these instances of virologic failure. Although all participants with virologic failure initially had CCR5-tropic virus, repeat testing after failure identified CXCR4-tropic virus; this may explain the treatment failure, although that link is also unclear. [#] [#]

Further study of the effect of mutations on viral resistance to vicriviroc has found that mutations in the V3 loop stem introduce resistance to vicriviroc and cross resistance to TAK779, another investigational CCR5 antagonist agent. Increased susceptibility to HGS004, a third investigational CCR5 antagonist agent, likely was caused by decreased binding of vicriviroc to the CCR5 receptor. [#]]]>
[#] [#] In a Phase II study of vicriviroc that was conducted in 118 treatment-experienced patients, 4 cases of lymphoma and 1 case of stomach cancer occurred in the vicriviroc-treated group. A causal association between vicriviroc and the lymphoma cases could not be established at the time, and all those who developed cancers had very advanced HIV disease. [#]

In another Phase II, dose-escalating study of vicriviroc, there were no significant differences in Grade 3 or 4 adverse events across the vicriviroc and placebo groups, but eight patients randomly assigned to receive vicriviroc 5 mg and two patients randomly assigned to receive placebo developed malignancies. The relationship of malignancy development to vicriviroc is uncertain. The study consequently was unblinded in March 2006, and the 5-mg dose group was discontinued. [#] [#] [#]

A safety evaluation of 116 participants enrolled on the Phase II VICTOR-E1 trial showed no safety concerns after a mean duration of 14 weeks (range of 12 to 28 weeks) of treatment with vicriviroc 20 or 30 mg compared with placebo. Specifically, no hepatotoxicity, malignancies, or drug-related seizures were noted. At Week 48, vicriviroc was well tolerated in both treatment arms, and Grade 3/4 adverse events occurred in approximately 20% of these and the placebo arms. Vicriviroc 20 mg and 30 mg administered once daily in combination with a ritonavir-boosted, PI-containing ART regimen appear well tolerated in this treatment-experienced population. [#] [#]

Safety data at Week 24 of an ongoing Phase III trial showed no evidence of safety concerns regarding cardiac toxicity, hepatotoxicity, drug related seizures, infections or malignancy; most adverse events were mild to moderate and were similar to placebo. The most common adverse events included nausea, headache, and fatigue. [#] [#] Other common adverse events noted in 2-year follow-up of Phase II studies included pharyngitis, abdominal pain, and fatigue. Fatigue was the only Grade 3 adverse event reported in more than 1% of the participants. [#]]]>
[#] ]]>[#] ]]> Gulick RM, Su Z, Flexner C, Hughes MD, Skolnik PR, Wilkin TJ, Gross R, Krambrink A, Coakley E, Greaves WL, Zolopa A, Reichman R, Godfrey C, Hirsch M, Kuritzkes DR; AIDS Clinical Trials Group 5211 Team. Phase II Study of the Safety and Efficacy of Vicriviroc, a CCR5 Inhibitor, in HIV-1-Infected, Treatment-Experienced Patients: AIDS Clinical Trials Group 5211. J Infect Dis. 2007;196:304-12.
Schaurmann D, Fautkenheuer G, Reynes J, Michelet C, Raffi F, van Lier J, Caceres M, Keung A, Sansone-Parsons A, Dunkle LM, Hoffmann C. Antiviral activity, pharmacokinetics and safety of vicriviroc, an oral CCR5 antagonist, during 14-day monotherapy in HIV-infected adults. AIDS. 2007 Jun 19;21(10):1293-9.
Strizki JM, Tremblay C, Xu S, Wojcik L, Wagner N, Gonsiorek W, Hipkin RW, Chou CC, Pugliese-Sivo C, Xiao Y, Tagat JR, Cox K, Priestley T, Sorota S, Huang W, Hirsch M, Reyes GR, Baroudy BM. Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2005 Dec;49(12):4911-9.
Wilkin TJ, Su Z, Kuritzkes DR, Hughes M, Flexner C, Gross R, Coakley E, Greaves W, Godfrey C, Skolnik PR, Timpone J, Rodriguez B, Gulick RM. HIV type 1 chemokine coreceptor use among antiretroviral-experienced patients screened for a clinical trial of a CCR5 inhibitor: AIDS Clinical Trial Group A5211. Clin Infect Dis. 2007 Feb 15;44(4):591-5. Epub 2007 Jan 17.
Gulick R, Zu S, Flexner C, et al. ACTG 5211: Phase 2 Study of the safety and efficacy of vicriviroc (VCV) in HIV+ treatment-experienced subjects: 48-week results. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia, Abstract TUAB102, 2007.
Safety and Effectiveness of the Oral HIV Entry Inhibitor SCH 417690 in HIV Infected Patients. Available at: Accessed 04/01/08.]]>
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100 USA
Phone: 908-423-1000

<![CDATA[Elvitegravir]]>[#] Integrase inhibitors are a new class of antiretrovirals that interfere with HIV replication by blocking viral ability to integrate into human cell genetic material. [#]]]>[#] Integrase inhibitors are a new class of antiretrovirals that interfere with HIV replication by blocking viral ability to integrate into human cell genetic material. [#]]]>[#] [#] [#]]]>[#]]]>EVG has been studied alone and in combination with low-dose ritonavir (RTV) at doses of 200, 400, and 800 mg twice daily (BID) and 50 and 800 mg once daily (QD). [#] Phase II studies in treatment-experienced patients have evaluated EVG dosed daily at 20, 50, and 125 mg in combination with ritonavir 100 mg. [#]

A Phase III trial of RTV-boosted EVG 150 mg (tablet) once-daily administered with a background regimen is ongoing.  For subjects randomized to the experimental treatment arm taking RTV-boosted atazanavir (ATV) or RTV-boosted lopinavir (LPV) as part of their background regimen, RTV-boosted EVG 85 mg (tablet) once-daily will be administered.[#]

Elvitegravir is also being evaluated in Phase III trials as part of a once-daily single-tablet “Quad” regimen containing EVG 150 mg, cobicistat 150 mg, emtricitabine (FTC) 200 mg and tenofovir disoproxil fumarate (TDF) 300 mg. [#] 

GS 9137 is a modified quinolone antibiotic with potent activity against HIV-1 in vitro. GS 9137 has the ability to bind magnesium cations. Integrase has a single binding site for magnesium, an ion required for strand transfer reactions and the assembly of integrase onto specific viral donor DNA. GS 9137 may be a selective inhibitor of the strand transfer process. [#] [#] GS 9137 retains antiretroviral activity against multiple drug--resistant HIV-1 in vitro. [#]

A Phase I pharmacokinetics study using single oral doses of GS 9137 was conducted in 32 healthy volunteers. Six patients in each group received daily GS 9137 doses of 100, 200, 400, or 800 mg without food or 400 mg with food. When administered with food, GS 9137 had a half-life of approximately 3.2 hours, compared with a fasting half-life of approximately 5.4 hours. The mean maximum plasma concentration (Cmax) achieved with food was 903 ng/mL; the mean area under the concentration-time curve (AUC) with food was 3,942 ng(h)/mL. The mean Cmax in a fasted state was 264 ng/mL, and the mean fasting AUC was 1,451 ng(h)/mL.  Mean time to maximum plasma concentration (tmax) in the fasted and fed states were 2.5 hr and 2.3 hr, respectively. Both Cmax and AUC increased across escalating daily doses of 100 to 800 mg in a less than dose-proportional manner. [#]

GS 9137 is mostly metabolized by the cytochrome P (CYP) 450 enzyme system, particularly CYP3A4. Glucuronidation is a minor metabolic pathway. Steady-state exposure and minimum plasma concentrations of GS 9137 increase 20-fold and 90-fold, respectively, with ritonavir boosting. Boosting also prolongs the half-life of GS 9137 to a maximum of 9.5 hours and a median of 7.6 hours. This allows for once-daily dosing of GS 9137. [#]

The minimum plasma concentration (Cmin) of GS 9137, rather than Cmax and AUC, appears more reflective of efficacy in pharmacokinetic models. This view is supported by a lower-than-expected antiviral effect with daily GS 9137 dosages of 800 mg; therefore, maintenance of effective trough concentrations is required for antiviral activity. Trough concentrations with once-daily ritonavir-boosted GS 9137 doses of 50 mg are estimated to remain above the 95% inhibitory concentration (IC95) for more than 48 hours post-dose. [#]

A randomized, double-blind, placebo-controlled trial in 40 HIV-1 infected patients not currently receiving antiretroviral therapy evaluated the effects of GS 9137 with food for 10 days. The following dosages were studied: 200, 400, and 800 mg BID; 800 mg QD; and 50 mg QD plus ritonavir 100 mg QD. In each dosage group, six patients received GS 9137, and two patients received placebo. All groups completed the 10-day dosing period and the 21 total days of evaluation, and all groups demonstrated significant antiviral activity compared with placebo. Twice-daily GS 9137 dosages of 400 or 800 mg and once-daily GS 9137 dosages of 50 mg plus ritonavir exhibited potent antiviral activity, with mean viral load reductions of at least 80-fold in each group. All patients achieved at least 50-fold viral load reduction, and half of the patients achieved at least 100-fold reduction. Maximum reductions were observed on days 10 or 11 in all but one patient. Once-daily GS 9137 dosages of 800 mg achieved a less than 10-fold viral load reduction, which was a statistically significant activity difference compared with these dosage groups. [#] [#]

Study GS-236-0101, a Phase I open-label, partially-randomized study evaluated two versions of a fixed-dose single tablet regimen containing either cobicistat (COBI) 100 mg or cobicistat 150  mg, each with EVG, FTC, and TDF versus RTV 100 mg-boosted EVG, FTC/TDF. Data indicate that the 150 mg cobicistat dose resulted in maintenance of targeted high EVG trough concentrations (Ctau) based on RTV-boosting.  Additionally, the fixed-dose combination tablet containing cobicistat 150 mg resulted in clinically equivalent tenofovir and FTC exposures compared to FTC/TDF administered individually. [#]

Study 183-0105 is a Phase II, randomized, dose-ranging trial of once-daily GS 9137 assessing noninferiority of GS 9137 to boosted comparator protease inhibitors (PIs) in HIV-infected participants. Patients were randomized to receive either once-daily GS 9137 20 mg (n=71), 50 mg (n=71), or 125 mg (n=73), each with RTV 100 mg, or boosted comparator PIs (CPI/r) (n=63), all in combination with an optimized background regimen of two or more nucleoside reverse transcriptase inhibitors (NRTIs) with or without enfuvirtide (T-20). Patients receiving T-20 were stratified across treatment arms. The GS 9137 20-mg arm was closed after Week 8 because of high rate of virologic failure, and patients were offered 125 mg doses of GS 9137. The addition of PIs darunavir or tipranavir was permitted when new data showed a lack of drug interactions between both PIs and GS 9137. The primary endpoint of the study was time-weighted average change from baseline in HIV RNA loads through 24 weeks (DAVG24). The mean DAVG24 for patients in the GS 9137 50 mg arm was -1.4 log copies/mL versus -1.2 log copies/mL for the comparator arm (p=0.27). For patients receiving GS 9137 125 mg versus the comparator arm, the mean DAVG24 was -1.7 log copies/mL and -1.2 log copies/mL, respectively; (p=0.02). In the GS 9137 125 mg group, patients receiving T-20 for the first time, or those who had one or more active NRTIs in their background therapy, experienced significantly greater mean reductions in viral load at 24 weeks compared to those with no active NRTIs and no first use of T-20 (-2.1 log copies/mL versus -0.7 log copies/mL, respectively; p <0.001).At Week 16, 38% of the 50-mg arm and 40% of the 125-mg arm had viral load levels less than 50 copies/mL, compared with 30% in the control arm. At Week 24, viral load levels less than 50 copies/mL were reported in 32% and 36% of the 50-mg and 125-mg arms, respectively, compared with 27% of the control arm. [#] [#] [#] [#]

Study 236-0104 is a double-blind, randomized, active-controlled, 48-week Phase II trial evaluating the safety and efficacy of a fixed-dose single-tablet “Quad” regimen (EVG 150 mg/cobicistat 150 mg/FTC 200 mg/TDF 300 mg) (n=48) versus efavirenz 600 mg/FTC 200 mg/TDF 300 mg (Atripla) (n=23) among HIV-infected treatment-naïve adults.  The primary efficacy endpoint, the proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 24, was achieved by 90% of patients in the “Quad” arm and 83% of patients in the Atripla arm. Patients in the “Quad” group experienced a median increase in CD4 cell count of 123 cells/mm3 compared to a median increase of 124 cells/mm3 among Atripla patients at 24 weeks. Study investigators have reported that this study has low power for formal efficacy comparisons; however, efficacy of the “Quad” met statistical criteria of non-inferiority as compared to Atripla as defined by a pre-specified lower bound of the non-inferiority margin of -12%. At Week 48, 90% patients in the “Quad” arm and 83% of patients in the Atripla arm achieved HIV-1 RNA levels of less than 50 copies/mL. Patients taking the “Quad” versus Atripla patients experienced a mean increase in CD4 cell counts of 240 cells/mm3 compared to 162 cells/mm3, respectively, at 48 weeks. [#] [#] [#]

Study 236-0102 is a Phase III, randomized, double-blind trial evaluating the safety and efficacy of the “Quad” regimen (EVG 150 mg/cobicistat 150 mg/FTC 200 mg/TDF 300 mg) versus Atripla in HIV-1 infected, antiretroviral treatment-naïve adults. The study met its primary objective, non-inferiority at week 48 as compared to Atripla. The primary efficacy endpoint, the proportion of subjects achieving and maintaining HIV-1 RNA less than 50 copies/mL through Week 48, was achieved by 88% of patients in the “Quad” group and 84% of patients in the Atripla arm (95% CI for the difference: -1.6% to 8.8%). The mean 48-week increase in CD4 cell count from baseline was 239 cells/mm3 and 206 cells/mm3, in the “Quad” arm and the Atripla arm, respectively (p=0.009). This study is ongoing in a blinded fashion. [#] [#]

A second pivitol “Quad” trial, Study 236-0103, a randomized, double-blind trial comparing the safety and efficacy of the “Quad” regimen versus RTV-boosted atazanavir and FTC 200 mg/TDF 300 mg (Truvada), is ongoing. [#] [#]

Study 145 is a Phase III, randomized, double-blind, 48-week clinical trial evaluating the non-inferiority of once-daily EVG 150 mg (n=351) versus twice-daily raltegravir (RAL) 400 mg (n=351), each administered with a background regimen in HIV-infected treatment-experienced adults with HIV RNA (viral load) of greater than or equal to 1,000 copies/mL. Patients have documented viral resistance, as defined by International AIDS Society-USA guidelines, or at least six months of treatment with two or more different classes of antiretroviral agents prior to screening. Background regimens are based on the results of resistance testing and include a fully-active RTV-boosted PI, and a second agent that may be a NRTI, etravirine, maraviroc or enfuvirtide. Because of known interactions, EVG patients whose background PI is either atazanavir or lopinavir receive an 85 mg dose of elvitegravir. The primary endpoint of this study was non-inferiority at Week 48 of EVG, dosed once daily, compared to RAL, dosed twice daily. Week 48 primary endpoint analysis indicated that 59.0 percent of patients in the EVG arm compared to 57.8 percent in the RAL arm (95% CI for the difference: -6.0% to +8.2%) achieved and maintained a viral load of less than 50 copies/mL. The predefined criterion for non-inferiority was a lower bound of a two sided 95% CI of -10 percent. Reported mean increase in CD4 cell counts was 138 cells/mm3 and 147 cells/mm3 in the EVG arm and the RAL arm, respectively. Twenty-six percent (16/62) of EVG patients developed integrase resistance compared to 20% (15/76) of patients in the RAL group. The blinded, randomized period of the study has been extended to up to 96 weeks. [#] [#]

Several resistance-conferring mutations, including E92Q, H51Y, S147G, and E157Q, have been observed during serial passage studies of GS 9137. The E92Q mutation occurred after 30 passages; the other mutations occurred after at least 60 passages. In addition, cross resistance was observed between GS 9137 and prior investigational integrase inhibitors. [#] A similar study compared GS 9137 susceptibility with zidovudine and the prior investigational integrase inhibitor L-870,810. Susceptibility of HIV-1 to GS-9137 and to L-870,810 decreased dramatically in the presence of two or three identified mutations. The E92Q mutation alone conferred resistance to GS-9137 and cross resistance to L-870,810. HIV susceptibility to GS 9137 was reduced 36-fold with the E92Q mutation alone. [#] [#] [#] Additional resistance mutations identified by in vitro culturing included T66I in the integrase catalytic core, R263K in the C-terminal DNA binding domain, S153Y, and F121Y. HIV susceptibility was reduced 15-fold with the T66I mutation and 98-fold with the combined T66I/R263K mutation. [#] [#]

A study using generated recombinant integrase proteins and viruses harboring raltegravir resistance mutations indicates that RAL resistance pathways involving mutations at integrase position 148 and 155 confer cross-resistance to EVG; however, EVG remains fully active against the Y143R mutant integrase and virus particles. [#]

In a single-blind, randomized, placebo-controlled trial, GS 9137 was safe and well tolerated in healthy participants; no Grade 3 or 4 adverse events occurred. One participant experienced mild anorexia, and one experienced increased liver enzyme levels; both problems resolved on their own. [#] A randomized, double-blind, placebo-controlled trial in HIV-infected participants also reported only mild adverse effects, with no Grade 3 or 4 events. [#] In a drug-interaction study of ritonavir-boosted GS 9137 and zidovudine, discontinuations included 2 of 24 participants who experienced headache and/or gastrointestinal symptoms, the onset occurring during the zidovudine-only dosing period. [#]

A randomized, double-blind, placebo-controlled trial of GS 9137 in 40 HIV-infected participants reported no dosage interruptions, discontinuations, or serious adverse events. Eight participants (27%) receiving GS 9137 and four (40%) receiving placebo experienced Grade 2 or 3 adverse events. Headache, occurring in three participants, was the only Grade 2 adverse event that occurred in more than one subject receiving GS 9137. Muscle spasm, the only Grade 3 adverse event in the treatment group, was experienced by one participant receiving twice-daily GS 9137 800 mg. Three participants receiving placebo and two receiving GS 9137 experienced a Grade 3 or 4 laboratory abnormality. These include two reports of Grade 3 elevated total amylase without an increase in serum lipase (one each in daily GS 9137 50 mg plus ritonavir and placebo), one Grade 3 elevated nonfasting triglyceride (one in twice-daily GS 9137 400 mg), a Grade 4 creatine kinase (placebo), and one Grade 3 alanine aminotransferase (placebo).[#]

Week 48 safety data from a Phase II trial, Study 236-0104, demonstrated a similar discontinuation rate and adverse events profile in both arms (“Quad” versus Atripla). Three patients discontinued treatment in each arm of the study. The rates of adverse events were similar between treatment arms; however, fewer central nervous system (CNS) side effects were observed among “Quad” patients. The most common adverse events reported in greater than 5% of patients in either treatment arm were abnormal dreams/nightmares, dizziness, fatigue, somnolence, diarrhea, headache, anxiety, nausea, abdominal distension and rash. There were two Grade 3 or 4 adverse events in the “Quad” group (pneumonia and anogenital warts) and two among Atripla patients (B-cell lymphoma with lymphadenopathy and neutropenia). A similar incidence of laboratory abnormalities (Grades 2-4) was reported across both arms of the study. Laboratory abnormalities seen in greater than 5% of subjects in either treatment arm included increases in amylase, hypercholesterolemia, creatine kinase changes, decreased neutrophils, and proteinuria. Similar mean changes in cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides occurred in both treatment groups. [#]

Study 236-0102 48-week data showed similar safety profiles between both the “Quad” arm and the Atripla-treated arm. The frequency of Grade 3-4 adverse events, laboratory abnormalities, and discontinuation rates due to adverse events were comparable in both arms of the study. [#]

In Study 145, a phase III trial comparing EVG dosed once daily to RAL dosed twice daily, adverse events, laboratory abnormalities, and discontinuation rates due to adverse events were reported as being comparable in both arms of the study at 48 weeks. [#] [#]

The absorption of GS 9137 increased approximately threefold when administered with food in a Phase I study. [#]

GS 9137 displays additive to highly synergistic antiviral activity in vitro with the following antiretroviral medications: lamivudine, lamivudine/zidovudine, zidovudine, tenofovir disoproxil fumarate (tenofovir DF), tenofovir DF/lamivudine, efavirenz, indinavir, and nelfinavir. [#]

Potential drug interactions have been studied between ritonavir-boosted GS 9137 (GS 9137/r) and zidovudine or emtricitabine/tenofovir DF for up to 10 days in healthy adults and between GS 9137/r and single doses of didanosine, stavudine, or abacavir. No clinically relevant interactions were observed during GS 9137/r administration with these antiretroviral agents, and they may be coadministered without dose adjustments. [#] [#] [#]

Due to drug-drug interactions, a dose reduction of elvitegravir from 150 mg to 85 mg when coadministered with atazanavir/ritonavir or lopinavir/ritonavir is necessary. [#]

When administering elvitegravir/r plus maraviroc, elvitegravir and ritonavir dose modifications are not needed; however, a reduced 150 mg dose of maraviroc is recommended. [#]

[#] ]]>[#]]]>[#]]]> DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, Elion R, Farthing C, Zhong L, Cheng AK, McColl D, Kearney BP; for the 183-0101 Study Team. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr. 2006 Sep;43(1):1-5.
Lataillade M, Kozal MJ. The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDS. 2006 Jul;20(7):489-501.
Ramanathan S, Shen G, Hinkle J, Enejosa J, Kearney BP. Pharmacokinetics of coadministered ritonavir-boosted elvitegravir and zidovudine, didanosine, stavudine, or abacavir. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):160-6.
Sato M, Motomura T, Aramaki H, Matsuda T, Yamashita M, Ito Y, Kawakami H, Matsuaki Y, Watanabe W, Yamataka K, Ikeda S, Kodama E, Matsuoka M, Shinkai H. Novel HIV-1 Integrase Inhibitors Derived from Quinolone Antibiotics. J Med Chem 2006 Mar 9;49(5):1506-8.
Shimura K, Kodama E, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, Watanabe Y, Ohata Y, Doi S, Sato M, Kano M, Ikeda S, Matsuoka M. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137).
Zolopa AR, Berger DS, Lampiris H, Zhong L, Chuck SL, Enejosa JV, Kearney BP, Cheng AK. Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial. J Infect Dis 2010; 201:814–22.
German P, Warren D, West S, Hui J, Kearney BP. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J Acquir Immune Defic Syndr. 2010 Nov 1;55(3):323-9.
Métifiot M, Vandegraaff N, Maddali K, Naumova A, Zhang X, Rhodes D, Marchand C, Pommier Y. Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143. AIDS. 2011 Jun 1;25(9):1175-8.
Ramanathan S, Mathias AA, German P, Kearney BP. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet. 2011 Apr 1;50(4):229-44.
Ramanathan S, Abel S, Tweedy S, West S, Hui J, Kearney BP. Pharmacokinetic interaction of ritonavir-boosted elvitegravir and maraviroc. J Acquir Immune Defic Syndr. 2010 Feb 1;53(2):209-14.]]>
<![CDATA[BMS-378806]]>[#] [#] ]]>[#] [#] ]]>[#] BMS-378806 is also being investigated in formulations for vaginal administration for the prevention of HIV-1 transmission when used in combination with other vaginal microbicides. [#] ]]>[#] ]]>[#] ]]>[#] Binding of gp120 is the first step of HIV infection at the cellular level; BMS-378806 appears to be the first compound to block this binding. [#]

BMS-378806 shows good oral bioavailability in animals and has low protein binding. It is active against viral strains with both the CCR5 and the CXCR4 coreceptors and is selective for HIV-1, specifically subtype B. [#] [#]

BMS-378806 retains activity against HIV strains resistant to protease inhibitors and reverse transcriptase inhibitors. [#] Resistance maps to substitutions located primarily near the CD4 binding sites of gp120, including A204D, F423Y, M434/I/V/T, and M475I. Other reported mutations include M475I, M434I/V, M426L, D350K, D185N, K655E, 1595F, V68A, and S440R. [#]

BMS-378806 has recently been tested as a topically administered vaginal microbicide in combination with other investigational entry inhibitors. BMS-378806 and CMPD 167 appear to be synergistic in vitro, inhibiting different stages of the viral-cell attachment and entry process. [#] When combined in vitro, CMPD167, C52L, and BMS-378806 inhibited infection of T cells and cervical tissue explants. Significant protection was achieved in macaques when BMS-378806 was used alone and in combination, even when applied up to 6 hours before challenge. [#] [#] ]]>
[#] No significant cytotoxicity has been noted. [#] ]]>[#] ]]>[#] ]]>Ketas TJ, Schader SM, Zurita J, Teo E, Polonis V, Lu M, Klasse PJ, Moore JP. Entry inhibitor-based microbicides are active in vitro against HIV-1 isolates from multiple genetic subtypes. Virology. 2007 Aug 1;364(2):431-40. Epub 2007 Apr 10.
Lin, PR. A Small Molecule HIV-1 Inhibitor That Targets the HIV-1 Envelope and Inhibits CD4 Receptor Binding. Proc Natl Acad Sci USA 2003;100(19):11013-8.
Veazey RS, Klasse PJ, Schader SM, Hu Q, Ketas TJ, Lu M, Marx PA, Dufour J, Colonno RJ, Shattock RJ, Springer MS, Moore JP. Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature 2005 Nov 3;438(7064):99-102.
Madani N, Hubicki A, Ng D, Smith A, Sodroski J. The road to finding potent HIV-1 entry inhibitors: Lessons learned from requirements for BMS-806 binding to HIV-1 envelope glycoprotein. 16th International AIDS Conference, Toronto, Canada, Abstract MOPE0001, 2006. ]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
<![CDATA[Carbomer 974]]>[#] Carbomer 974, a cross-linked polyacrylic acid, is highly negatively charged, containing thousands of ionizable carboxyl groups per molecule, and has a molecular weight of several billion. These carboxyl groups can release hydrogen ions, the active agents that provide the acid-buffering action of BufferGel. [#] In addition, these carboxyl groups, with the polymer's high molecular weight, prevent transmucosal absorption of the buffer agent. Moreover, as a polymeric buffer, the product will not become hypertonic when high concentrations of buffer material are used and will not cause the cytotoxicity that is seen with use of small, absorbable buffers such as acetic or lactic acid. [#] [#] ]]>[#] Carbomer 974, a cross-linked polyacrylic acid, is highly negatively charged, containing thousands of ionizable carboxyl groups per molecule, and has a molecular weight of several billion. These carboxyl groups can release hydrogen ions, the active agents that provide the acid-buffering action of BufferGel. [#] In addition, these carboxyl groups, with the polymer's high molecular weight, prevent transmucosal absorption of the buffer agent. Moreover, as a polymeric buffer, the product will not become hypertonic when high concentrations of buffer material are used and will not cause the cytotoxicity that is seen with use of small, absorbable buffers such as acetic or lactic acid. [#] [#] ]]>[#] [#] ]]>[#] [#] Two contraceptive trials of more than 1,200 women showed BufferGel combined with a diaphragm to be non-inferior to Gynol II (a nonoxynol-9 based spermicide) used with a diaphragm. [#] [#]

In addition, carbomer 974 blocks the alkalinizing action of semen that enables acid-sensitive pathogens that cause sexually transmitted diseases (STDs) to transmit infection. [#] Carbomer 974 is effective in vitro against herpes simplex viruses, Chlamydia trachomatis, Neisseria gonorrhea, and other STD pathogens. [#]

In a pilot study of 10 women, BufferGel was moderately effective as a treatment for bacterial vaginosis. [#] An international, Phase I study of BufferGel as a contraceptive reported an 80% decrease in prevalence of bacterial vaginosis in women using the drug once daily for 1 week. [#]

Carbomer 974 polymer also is used as a gelling or tableting agent in many pharmaceuticals. [#] ]]>
[#] ]]>[#]

BufferGel contains 5% carbomer 974. [#] In Phase II studies, BufferGel is packaged as a single-use, prefilled applicator to be administered up to 60 minutes prior to sexual intercourse. [#] ]]>
[#] ]]>
[#] [#] Carbomer 974 is formulated to buffer the concentration of free hydrogen ions at 0.1 mM, the level normally found in the vaginal lumen (pH 3.8 to 4.0). Hydrogen ions are buffered by the carboxyl groups that occur in large quantities on the carbomer 974 polymer. Carbomer 974 acidifies semen to a pH less than or equal to 5. [#] In vitro, sperm and many STD pathogens are inactivated at a pH less than 5. HIV specifically is inactivated in the acidic environment below pH 4 to 5.8. [#]

BufferGel is being compared with another investigational microbicide agent, PRO 2000 gel, in a Phase II/IIb, four-arm, randomized, single-blind, placebo-controlled trial. Unlike BufferGel, PRO 2000 inhibits viral entry into cells. Participants will be given single-dose, prefilled applicators of gel containing BufferGel, PRO 2000, placebo gel, or no treatment to use intravaginally up to 60 minutes before each act of intercourse. [#] [#] ]]>

An international Phase I clinical trial had similar results. Adverse events were categorized as mild to moderate and included presence of Candida on wet mount, vaginal and vulvar itching or burning after gel insertion or when passing urine, labial rash, lower abdominal pain, and vaginal discharge. Irritation was reported in approximately 25% of women in the study and was generally mild and of short duration. Epithelial abnormalities detected by pelvic exam or colposcopy were uncommon. [#] In both trials, adverse effects of BufferGel were generally self limiting and readily resolved. Both trials reported a high degree of compliance and acceptability. [#] [#]

In a Phase I clinical trial of penile application of BufferGel, no serious adverse events or urethral inflammation were reported, and adverse event rates were not significantly different from placebo. [#]

In two Phase I trials of BufferGel conducted in 125 women, a significant decrease in bacterial vaginosis was noted, along with some self-limiting, local genitourinary signs and symptoms, including erythema, pruritis, and dysuria. [#] ]]>
[#] ]]>[#] ]]>[#] [#] ]]>[#] [#] ]]> -BufferGel and PRO 2000/5: Vaginal Gels to Prevent HIV Infection in Women. Available at: Accessed 01/14/09.
Bentley ME, Fullem AM, Tolley EE, Kelly CW, Jogelkar N, Srirak N, Mwafulirwa L, Khumalo-Sakutukwa G, Celentano DD. Acceptability of a microbicide among women and their partners in a 4-country phase I trial. Am J Public Health. 2004 Jul;94(7):1159-64.
Cone RA, Hoen T, Wong X, Abusuwwa R, Anderson DJ, Moench TR. Vaginal microbicides: detecting toxicities in vivo that paradoxically increase pathogen transmission. BMC Infect Dis. 2006 Jun 1;6:90.
Dahwan D, Mayer KH. Microbicides to prevent HIV transmission: overcoming obstacles to chemical barrier protection. J Infect Dis 2006;193:36-44.
Harwell JI, Moench T, Mayer KH, Chapman S, Rodriguez I, Cu-Uvin S. A pilot study of treatment of bacterial vaginosis with a buffering vaginal microbicide. J Womens Health (Larchmt). 2003 Apr;12(3):255-9.
Tabet SR, Callahan MM, Mauck CK, Gai F, Coletti AS, Profy AT, Moench TR, Soto-Torres LE, Poindexter III AN, Frezieres RG, Walsh TL, Kelly CW, Richardson BA, Van Damme L, Celum CL. Safety and acceptability of penile application of 2 candidate topical microbicides: BufferGel and PRO 2000 Gel: 3 randomized trials in healthy low-risk men and HIV-positive men. J Acquir Immune Defic Syndr. 2003 Aug 1;33(4):476-83. Erratum in: J Acquir Immune Defic Syndr. 2003 Sep 1;34(1):118.]]>
Baltimore, MD 21286
Phone: 410-516-7260
Fax: 410-516-6597]]>
Wickliffe, OH 44092
Phone:  440-943-4200]]>
<![CDATA[Carrageenan]]>[#] [#] The kappa, iota, and lambda forms of carrageenan are distinguished by the position of sulfate and the presence or absence of anhydrogalactose on the main polysaccharide backbone. Carrageenan is a mixture of lambda and kappa carrageenan. Kappa carrageenans have a helical tertiary structure that allows gelling; lambda carrageenans are non-gelling. [#] ]]>[#] [#] The kappa, iota, and lambda forms of carrageenan are distinguished by the position of sulfate and the presence or absence of anhydrogalactose on the main polysaccharide backbone. Carrageenan is a mixture of lambda and kappa carrageenan. Kappa carrageenans have a helical tertiary structure that allows gelling; lambda carrageenans are non-gelling. [#] ]]>[#] [#] [#] Carrageenan is also being studied in combination with other investigational microbicide agents. [#]

A recently completed, randomized, double-blind, Phase III trial compared carrageenan gel with placebo in more than 6,000 women. However, the study did not find carrageenan statistically significantly more effective than placebo at preventing HIV transmission because of the high rate of HIV infection in both arms. [#] ]]>
[#] Carrageenan is used as a clarifier for beverages and is used to suspend cocoa in chocolate manufacturing. [#] Carrageenan is used in cough and cold preparations, topical creams, and medicated shampoos. Carrageenan compounds are on the FDA's list of GRAS (generally recognized as safe) products for consumption and topical application. [#]

Carrageenan is a potent in vitro inhibitor of herpes simplex virus, human cytomegalovirus, vesicular stomatitis virus, and Sindbis virus, in addition to HIV. [#] Laboratory tests have shown that carrageenan gel also blocks human papillomavirus and gonorrhea infection in vitro and in vivo. [#] ]]>
[#] ]]>[#] [#]

Prefilled, single-dose, disposable, plastic Micralax® applicators providing delivery of approximately 4 mL gel. [#] ]]>
[#] [#] In one study, carrageenan reduced the number of macrophages in lymph nodes by greater than 90% compared to a 50% reduction by placebo. [#] Carrageenan appears to prevent cell trafficking by coating the surfaces of vaginal cells to prevent adhesion of macrophages to the epithelial surface. [#]

Carrageenan is bound to the vaginal epithelium for up to 4 hours. An in vivo study showed that significant quantities of carrageenan could be detected up to 24 hours post-application, and that the duration of activity was retained without loss for 3 hours. [#]

Carrageenan gel studied in cervical samples did not appear to interfere with testing for other sexually transmitted diseases. [#] ]]>
[#] No women developed visible cervical or vaginal abnormalities. [#] Most women considered the applicator and the gel itself easy to use, not messy, and of reasonable volume. [#] [#] No significant differences in rate of side effects or development of lesions were noted between gel and placebo users. [#]

In a Phase II trial of 55 HIV uninfected couples who used the gel or a placebo prior to each act of intercourse, no differences in side effects were reported in men exposed to the microbicide compared to those exposed to placebo. [#]

In vitro comparison of carrageenan and nonoxynol-9 (N-9) showed carrageenan to be 20- to 50-fold less toxic than N-9 to cervical and colorectal epithelial cells. [#]

In a recently completed Phase III clinical trial, carrageenan was studied for 2 years and was found safe for vaginal use throughout that time. Adverse effects from carrageenan use were not different than with placebo and were considered minor. [#] [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>D'Cruz OJ, Uckun FM. Clinical development of microbicides for the prevention of HIV infection. Curr Pharm Des. 2004;10(3):315-36. Review. PMID: 14754390
Perotti ME, Pirovano A, Phillips DM. Carrageenan formulation prevents macrophage trafficking from vagina: implications for microbicide development. Biol Reprod. 2003 Sep;69(3):933-9.
Kilmarx PH, Supawitkul S, Yanpaisarn S, Jones H, van de Wijgert J, Young NL, Srivirojana N, Guest P. A year-long, randomized, controlled clinical trial of a carrageenan gel as a vaginal microbicide: Effect on reproductive tract infection (RTI) rates. International AIDS Conf, Barcelona. Abstract WeOrD1318. 2002.
Morar NS, Braunstein S, Jones H, Moodley M, Aboobaker J, Ndaba M, Ndlovu G, van de Wijgert J, Ramjee G. Safety of Carraguard® among HIV-positive women and men in South Africa. Microbicides Conf, London. Abstract 02463. 2004.]]>
Philadelphia, PA 19103
Phone: 800-526-3649
Fax:  215-299-6291]]>
Weiss Research Building
1230 York Avenue
New York, NY 10021]]>
Weiss Research Building
1230 York Avenue
New York, NY 10021]]>
<![CDATA[Cellulose sulfate]]>[#] It is a noncytotoxic, antifertility agent that exhibits in vitro antimicrobial activity against sexually transmitted pathogens, including HIV. [#] ]]>[#] It is a noncytotoxic, antifertility agent that exhibits in vitro antimicrobial activity against sexually transmitted pathogens, including HIV. [#] ]]>[#] One trial in HIV uninfected women being conducted in South Africa, Benin, Uganda, and India was halted because preliminary results at some trial sites indicated using the microbicide could lead to potential increased risk of HIV infection in these women. Simultaneously, a Nigerian study of cellulose sulfate was halted. Although the second study did not detect an increased risk of HIV infection associated with the microbicide, the trial was halted as a precautionary measure in light of the preliminary results from the first study. [#] At interim analysis of the first trial, 24 women using cellulose sulfate and 11 women using placebo developed HIV. Possible causes for the increased infection rate include inflammatory reactions, local immune dysfunction, or vaginal flora disruption. [#] [#] After the final study visit, conducted in May 2007, analysis showed no statistically significant difference in onset of HIV infection (25 women using cellulose sulfate and 16 using placebo) and no potential to prevent HIV transmission. [#] The final study report concludes that cellulose sulfate has no role as an HIV prevention method. [#] ]]>[#] [#]

Cellulose sulfate displays direct microbicidal activity against human papillomavirus in vitro. [#] In January 2006, Polydex Pharmaceuticals received a European patent regarding the use of cellulose sulfate and other sulfated polysaccharides to prevent and treat papilloma virus infections in humans and other mammals. The patent acknowledges that microbicidal agents that may otherwise have a broad spectrum of prevention capabilities have thus far been ineffective against papilloma viruses. [#]

Two CONRAD-sponsored studies tested contraceptive activity of cellulose sulfate, and both efficacy trials ended in 2006. [#] One of these studies tested the contraceptive effectiveness of cellulose sulfate in preventing pregnancy when used by a woman in a sexually active, HIV uninfected couple for 6 months. [#] Results found that the chance of pregnancy in 6 months among typical users of cellulose sulfate was 13.4% and the chance of pregnancy in 6 menstrual cycles of perfect use of cellulose sulfate was 3.9%. [#]

In vitro, cellulose sulfate inhibits Gardnerella vaginalis and anaerobes that cause bacterial vaginosis (BV). [#] [#] BV may act as a cofactor in the heterosexual transmission of HIV, so the impact of cellulose sulfate and other vaginal microbicides on BV warrants evaluation. [#] Because cellulose sulfate inhibits BV pathogens, cellulose sulfate may provide contraceptive and antimicrobial activity without increasing a patient's risk of BV. [#]

Studies have also been conducted to test the safety of cellulose sulfate in conjunction with use of a diaphragm and magnetic resonance imaging (MRI). [#] ]]>
[#] ]]>[#] [#]

Cellulose sulfate 200-mg vaginal tablets containing excipients generally regarded as safe (GRAS). Tablets disintegrate in less than 30 seconds in 10 mL of fluid to form a smooth, homogenous, viscous, and bioadhesive dispersion. [#]

Cellulose sulfate 6% vaginal gel has been tested in women up to four times daily for up to 14 consecutive days. [#] [#] [#]

Cellulose sulfate 0.1% vaginal gel has been tested for contraceptive use. [#]

Because the optimal applied volume of gel is not known, volumes ranging from 2.5 to 5 mL have been tested. [#] ]]>
[#] Cellulose sulfate gel 6% has been shown to stimulate acrosomal loss, inhibit hyaluronidase, and impede sperm penetration into cervical mucus in vitro. [#] Cellulose sulfate inhibits HIV entry and sperm-egg interaction in vitro, reaching 95% or greater inhibition of sperm binding capacity at a concentration of 1 mg/mL. Cellulose sulfate does not affect sperm motility and is not cytotoxic. [#] [#] Cellulose sulfate inhibits HIV-1 strains with a 50% inhibitory concentration (IC50) of 50 ug/mL. It is especially effective against HSV-1 and -2 at an IC50 of 0.12 to 0.25 ug/ml. [#]

Linear gel spread, as evaluated in a study of 2.5 mL and 3.5 mL gel volumes inserted vaginally, takes place primarily in the first 5 minutes after gel insertion. Lateral spreading (surface contact) appears to continue after linear spreading slows or stops. Upright patient movement has a greater effect on gel distribution than gel volume does. Using a larger gel volume increases linear spreading but provides less consistent lateral spreading. The greatest linear and lateral spreading have been noted 50 minutes after insertion in women using 3.5 mL of gel who have walked around after insertion. Even under these conditions, women had bare spots in coverage, particularly in the proximal vagina. Thus, the spreading of cellulose sulfate without intercourse did not result in complete vaginal coverage, even at 50 minutes after product insertion. [#]

Vaginal cellulose sulfate tablet inhibition of sperm enzyme and of HIV, HSV, and Chlamydia appears comparable to that of the gel formulation. Cellulose sulfate tablets do not inhibit Lactobacillus in vitro. [#]

In rabbit models, cellulose sulfate 6% gel was active as a contraceptive for at least 18 hours after application and was partially active for at least 24 hours. A gel concentration as low as 0.1% was an effective contraceptive when applied within 30 minutes of insemination. [#] ]]>

Previous results from 11 cellulose sulfate studies sponsored by CONRAD have indicated the microbicide is safe, acceptable, and effective as currently marketed spermicides and sexual lubricants. These 11 studies include 5 safety studies in women,2 safety studies in men, 2 contraceptive effectiveness studies, and studies testing the safety of the microbicide when used with a diaphragm and MRI. [#]

Cellulose sulfate 6% gel administered vaginally four times daily for 14 days did not differ with respect to epithelial disruption, candidiasis, BV, and acceptability from K-Y jelly placebo. [#] A blinded crossover study of 6% gel was conducted with 2.5 and 3.5 mL volumes. Each woman used each gel volume twice; after one application, women had restricted upright movement, and after the other, they were allowed to walk around. Excessive leakage was not noted with either volume. [#]

In a safety and acceptability study conducted in the United States and the Dominican Republic, HIV uninfected women used cellulose sulfate 6% gel or K-Y jelly placebo twice daily for 14 days. Some level of product leakage was reported by all study participants. There was no noticeable difference in the proportion of overall vaginal leakage of moderate or severe intensity between the cellulose sulfate and K-Y jelly placebo groups. [#]

In a Phase I, two-part cohort study of 180 women in India, Nigeria, and Uganda using cellulose sulfate 6% gel or K-Y jelly placebo, the majority of women had no problem with either gel, and most found the gels easy to use. Fewer women using cellulose sulfate than using K-Y jelly placebo reported genital symptoms in Cohort 1; new colposcopic findings were detected in only 9% of women using cellulose sulfate, compared to 21% of women using K-Y jelly. In Cohort 2, fewer women using cellulose sulfate than using K-Y jelly placebo reported genital symptoms; 11% in each group had new colposcopy findings. Differences between the groups were not considered to be statistically significant. [#]

In a survey study of HIV infected women using 6% gel once or twice daily for 14 days, women liked the gel's color, smell, and consistency somewhat to a lot. Overall, 31% of women reported that the gel soiled clothing or bed linens. In women using the gel once daily, 4 out of 7 reported leakage during sex; 4 out of 7 also reported leakage after sex. Many women reported that they would prefer a microbicide that could go unnoticed by a sex partner. Primary issues with the gel were soiling of clothes and leakage of gel during sex. [#]

In a Phase I trial in which men directly applied either cellulose sulfate gel or an active control containing nonoxynol-9 for 7 consecutive days, the cellulose sulfate gel was not more irritating than the active control. Symptoms reported by one patient after using cellulose sulfate included slight stinging and mild tingling. [#]

One South African clinical trial tested the safety of the Ortho All flex diaphragm when used with cellulose sulfate gel or with K-Y jelly, compared with cellulose gel use alone, over 6 months in HIV uninfected women. Very few of the participants in this study had ever used diaphragms before. This combination was found to be safe with no serious adverse events or adverse events related to diaphragm use reported. Colposcopic findings were observed in 60% to 80% of study participants. Seven severe findings were observed in those using the microbicide in combination with the diaphragm; however, these differences were not statistically significant. The location of these findings on the external genitalia suggest that they may have been due to trauma following diaphragm insertion. [#]

Cellulose sulfate vaginal tablets are not cytotoxic. The gel formulation has shown an acceptable safety profile in macaques. [#] [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>Anderson RA, Feathergill K, Diao XH, Chany C 2nd, Rencher WF, Zaneveld LJ, Waller DP. Contraception by Ushercell (cellulose sulfate) in formulation: duration of effect and dose effectiveness. Contraception. 2004 Nov;70(5):415-22.
Cheshenko N, Keller MJ, MasCasullo V, Jarvis GA, Cheng H, John M, Li JH, Hogarty K, Anderson RA, Waller DP, Zaneveld LJ, Profy AT, Klotman ME, Herold BC. Candidate topical microbicides bind herpes simplex virus glycoprotein B and prevent viral entry and cell-to-cell spread. Antimicrob Agents Chemother. 2004 Jun;48(6):2025-36.
D'Cruz OJ, Uckun FM. Clinical development of microbicides for the prevention of HIV infection. Curr Pharm Des. 2004;10(3):315-36. Review.
El-Sadr WM, Mayer KH, Maslankowski L, Hoesley C, Justman J, Gai F, Mauck C, Absalon J, Morrow K, Masse B, Soto-Torres L, Kwiecien A. Safety and acceptability of cellulose sulfate as a vaginal microbicide in HIV-infected women. AIDS. 2006 May 12;20(8):1109-16.
Schwartz JL, Mauck C, Lai JJ, Creinin MD, Brache V, Ballagh SA, Weiner DH, Hillier SL, Fichorova RN, Callahan M. Fourteen-day safety and acceptability study of 6% cellulose sulfate gel: a randomized double-blind Phase I safety study. Contraception. 2006 Aug;74(2):133-40. Epub 2006 May 2.]]>
83 Shirley Street
83 Shirley Street
<![CDATA[Cyanovirin-N]]>[#] ]]>[#] ]]>[#] It is in preclinical development as a microbicide for the prevention of sexual transmission of HIV. [#] ]]>[#] [#]

In studies in vitro and in mouse models, cyanovirin-N was active against the Zaire strain of the Ebola virus. [#] ]]>
[#] ]]>[#] ]]>[#]

Cyanovirin-N binds to certain high-mannose oligosaccharides (oligomannose-8 and oligomannose-9) on viral surface envelope glycoprotein gp120, blocking its interaction with cellular receptors. This unique and effectively irreversible interaction renders gp120 incapable of mediating virus-to-cell or cell-to-cell fusion. [#] [#] Cyanovirin interacts with one sugar at a primary binding site with high affinity and to another sugar (a secondary binding site) with low affinity. In addition, cyanovirin-N appears to bind to viral oligosaccharides with high affinity and to mammalian oligosaccharides with low affinity, potentially providing potent inactivation of HIV-1 and -2 without potent adverse effects to the body. [#]

Cyanovirin-N's anti-HIV effects are expressed during the initial binding or fusion process. These effects may occur after the initial virus-to-cell attachment phase, but prior to the completion of viral entry and replication. [#] ]]>
[#] ]]>Botos I, Wlodawer A. Cyanovirin-N: a sugar-binding antiviral protein with a new twist. Cell Mol Life Sci. 2003 Feb;60(2):277-87. Review. PMID: 12678493
Tsai CC, Emau P, Jiang Y, Agy MB, Shattock RJ, Schmidt A, Morton WR, Gustafson KR, Boyd MR. Cyanovirin-N inhibits AIDS virus infections in vaginal transmission models. AIDS Res Hum Retroviruses. 2004 Jan;20(1):11-18. PMID: 15000694
Tziveleka LA, Vagias C, Roussis V. Natural products with anti-HIV activity from marine organisms. Curr Top Med Chem. 2003;3(13):1512-35. PMID: 14529524]]>
Suite 200
South San Francisco, CA 94080
Phone: 650-616-2200]]>
<![CDATA[Hydroxyethyl cellulose]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>
Hydroxyethyl cellulose is being studied for its safety and use in clinical trials of microbicides. A proper base and placebo formulation is critical in the evaluation of safety and efficacy of active microbicide formulations. Efficacy of a microbicide would be underestimated if the placebo itself provided a degree of protection. A placebo with epithelial toxicity that increased susceptibility would cause an overestimation of microbicide efficacy. A useful placebo must be stable without altering the active drug, and it itself must be safe and well tolerated. A recent study demonstrated the safety, stability, inactivity, and efficacy of hydroxyethyl cellulose as a universal placebo for clinical trials of microbicides. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>Tien D, Schnaare RL, Kang F, Cohl G, McCormick TJ, Moench TR, Doncel G, Watson K, Buckheit RW, Lewis MG, Schwartz J, Douville K, Romano JW. In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials. AIDS Res Hum Retroviruses. 2005 Oct;21(10):845-53.
An Imaging Trial of the Distribution of Topical Gel in the Human Vagina: Assessment of Bare Spots. Available at: Accessed 09/26/07.
Imaging Trial of the Distribution of Topical Gel in the Human Vagina: Enhanced MRI Techniques to Increase Resolution. Available at: Accessed 09/26/07. ]]>
39 Old Ridgebury Road
Danbury, CT 06817-0001]]>
39 Old Ridgebury Road
Danbury, CT 06817-0001]]>
<![CDATA[PRO 2000]]>[#] [#] ]]>[#] [#] ]]>[#] It is being studied in Phase II/IIb and Phase III trials for safety and efficacy. [#] ]]>[#] ]]>[#] ]]>[#] In Phase II/IIb and III studies, 0.5% formulations of PRO 2000 are being investigated. [#] ]]>[#] ]]>[#] PRO 2000 binds to CD4 with nanomolar affinity and blocks CD4 binding to HIV gp120. It inhibits infection by a wide range of HIV isolates in a variety of cell types. [#]

Following topical administration of naphthalene 2-sulfonate polymer in animals and intravaginal application in humans, no systemic absorption was detected. [#] PRO 2000 was undetectable in plasma samples collected from three separate Phase I studies, suggesting that negligible systemic absorption of PRO 2000 occurs following intravaginal administration. [#] [#]

PRO 2000 is completely compatible with the use of latex condoms. This may offer women an appealing alternative or complement to condoms, providing women with a means to control disease transmission. PRO 2000 has demonstrated greater safety in use than nonoxynol-9 spermicides, which have been shown to increase users' risk of contracting HIV and other sexually transmitted diseases; it is also highly stable, easy to store, and easy to apply. [#]

In a randomized trial comparing 5% PRO 2000 to inactive placebo for 14 days in 24 HIV negative women, levels of cytokines, interleukin-1 receptor antagonist, immunoglobulins, and human beta-defensin 2 secreted into the blood were lower in the PRO 2000 arm compared with the placebo group. [#] In contrast, in a study comparing PRO 2000, placebo, and nonoxynol-9, mice receiving intravaginal nonoxynol-9 experienced increased inflammatory responses, whereas mice treated with PRO 2000 experienced responses similar to placebo and responded with minimal inflammation. [#]

Cervicovaginal lavage has been performed in a randomized study to identify activity of PRO 2000 after vaginal application. This study found that 0.5% PRO 2000 retains substantial anti-HIV activity after vaginal application and remains sufficiently bioavailable. [#]

An ongoing Phase II/IIb trial is evaluating the safety and efficacy of 0.5% PRO 2000 compared with placebo, and an ongoing Phase III trial is evaluating the safety and efficacy of 0.5% PRO 2000 compared with placebo. [#] [#] ]]>

In a Phase I trial of 63 sexually active HIV uninfected women and abstinent HIV infected women, no serious adverse events were reported. Seventy-three percent of participants experienced at least 1 adverse event, of which 82% were classified as mild. [#] In a second Phase I trial of 73 abstinent HIV uninfected women, three women developed cervical abrasion. In both trials, the 0.5% gel formulation was better tolerated than the 4% gel formulation. [#]

During a Phase I safety and acceptability study of penile application of PRO 2000, no serious adverse events or urethral inflammation were reported following a week of daily PRO 2000 application in 72 HIV uninfected and 25 HIV infected men. Seventeen percent of uninfected participants and 4% of infected participants reported at least 1 mild adverse event. [#]

In a Phase I safety and acceptability study of the 0.5% gel formulation in 42 HIV uninfected women in Pune, India of low and higher risk for HIV transmission, 24 (57%) of the participants experienced at least 1 adverse event judged possibly related to product use. Of these 24, 7 (17%) participants experienced a moderate adverse event and 17 (40%) experienced only mild adverse events. No serious adverse events were observed. [#] ]]>
[#] ]]>[#] ]]>[#]

PRO 2000 is odorless and virtually colorless. [#] ]]>
[#] ]]>[#] ]]>
Galen GT, Martin AP, Hazrati I, Garin A, Guzman E, Wilson SS, Porter DD, Lira SA, Keller MJ, Herold BC. A comprehensive murine model to evaluate topical vaginal microbicides: mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety. Journal of Infectious Diseases 2007 May;195(9):1332-1339.
Keller MJ, Guzman E, Hazrati E, Kasowitz A, Cheshenko N, Wallenstein S, Cole AL, Cole AM, Profy AT, Wira CR, Hogarty K, Herold BC. PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity. AIDS 2007 Feb;21(4):467-476.
Scordi-Bello IA, Mosoian A, He C, Chen Y, Cheng Y, Jarvis GA, Keller MJ, Hogarty K, Waller DP, Profy AT, Herold BC, Klotman ME. Candidate sulfonated and sulfated topical microbicides: comparison of anti-human immunodeficiency virus activities and mechanisms of action. Antimicrob Agents Chemother. 2005 Sep;49(9):3607-15.
Ramjee G, Shattock R, Delany S, McGowan I, Morar N, Gottemoeller M. Short report: Microbicides 2006 Conference. AIDS Research and Therapy 2006, 3:25. Available at: Accessed 10/09/07.
An International Multi-Centre, Randomised, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of 0.5% and 2% PRO 2000/5 Gels for the Prevention of Vaginally Acquired HIV Infection. Available at: Accessed 10/09/07.
Phase II/IIb Safety and Effectiveness Study of the Vaginal Microbicides BufferGel and 0.5% PRO 2000/5 Gel (P) for the Prevention of HIV Infection in Women. Available at: Accessed 10/09/07.]]>
Newark, DE 19702 
Phone:  800-462-3636
Fax:  877-392-3636]]>
<![CDATA[SPL7013]]>[#] It is the active ingredient of VivaGel, a water-based vaginal microbicide gel. [#] ]]>[#] It is the active ingredient of VivaGel, a water-based vaginal microbicide gel. [#] ]]>[#] It is being studied for use as the active ingredient in VivaGel, a vaginal microbicide, in the prevention of vaginal transmission of HIV and genital herpes. [#] VivaGel is at the expanded safety/Phase IIa stage of clinical development and was granted fast-track status by the FDA in January 2006. [#]

A study to test VivaGel's safety, acceptability, and ease of use in healthy, sexually active young women in the United States and Puerto Rico began enrollment in July 2007. [#] [#]

A Phase I/II clinical trial is currently underway to investigate the timescale over which VivaGel retains activity against HIV and HSV-2, and the trial will measure the level of antiviral activity retained by VivaGel after vaginal administration. [#] ]]>

A Phase I study in healthy, sexually active American and Kenyan women to test VivaGel's safety and tolerability began enrollment in October 2006. [#] This trial is the first microbicide clinical development program specifically for the prevention of HSV-2 (genital herpes). [#]

In an independent study conducted at Johns Hopkins University, SPL7013 also exhibited a potent contraceptive effect when tested in animals. [#]

In mid-July 2007, Starpharma signed an agreement with a leading condom company in relation to the use of VivaGel as a condom coating. [#] ]]>
[#] ]]>[#] [#]

VivaGel would be used via a single-use, prefilled vaginal applicator. [#] ]]>
[#] [#]

A Phase I, double-blind, placebo-controlled trial evaluated the plasma absorption of SPL7013 in 36 healthy, sexually abstinent women. Women were assigned to 1 of 3 arms of 0.5, 1.0, and 3.0% gel, respectively, and all doses were administered once daily for 7 days. Eight women received active gel and four received placebo in each arm. Plasma samples after the first, third, fifth, and seventh doses showed no plasma SPL7013 levels, which confirmed localized activity of the drug. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#]

VivaGel: water-based gel. [#] ]]>
[#] ]]>
Gong E, Matthews B, McCarthy T, Chu J, Holan G, Raff J, Sacks S. Evaluation of dendrimer SPL7013, a lead microbicide candidate against herpes simplex viruses. Antiviral Res. 2005 Dec;68(3):139-46. Epub 2005 Sep 27.
Jiang YH, Emau P, Cairns JS, Flanary L, Morton WR, McCarthy TD, Tsai CC. SPL7013 gel as a topical microbicide for prevention of vaginal transmission of SHIV89.6P in macaques. AIDS Res Hum Retroviruses. 2005 Mar;21(3):207-13.
McCarthy TD, Karellas P, Henderson SA, Giannis M, O'Keefe DF, Heery G, Paull JR, Matthews BR, Holan G. Dendrimers as drugs: discovery and preclinical and clinical development of dendrimer-based microbicides for HIV and STI prevention. Mol Pharm. 2005 Jul-Aug;2(4):312-8. Review.
Rosa Borges A, Schengrund CL. Dendrimers and antivirals: a review. Curr Drug Targets Infect Disord. 2005 Sep;5(3):247-54. Review.
Lackman-Smith C, Osterling C, Luckenbaugh K, Mankowski M, Snyder B, Lewis G, Paull J, Profy A, Ptak RG, Buckheit RW Jr, Watson KM, Cummins JE Jr, Sanders-Beer BE. Development of a comprehensive human immunodeficiency virus type 1 screening algorithm for discovery and preclinical testing of topical microbicides. Antimicrob Agents Chemother. 2008 May;52(5):1768-81. Epub 2008 Mar 3.
Rupp R, Rosenthal SL, Stanberry LR. VivaGel (SPL7013 Gel): a candidate dendrimer--microbicide for the prevention of HIV and HSV infection. Int J Nanomedicine. 2007;2(4):561-6.]]>
St. Kilda Road Central
Melbourne, Victoria,
<![CDATA[Tenofovir]]>[#] ]]>[#] ]]>[#] studies as a vaginal microbicide for the prevention of HIV transmission. Tenofovir is also being studied in combination with PRO 2000, another investigational vaginal microbicide. [#] [#] Approved oral formulations of its prodrug, tenofovir disoproxil fumarate (tenofovir DF), are used to treat HIV. [#] ]]>[#] [#] Tenofovir disoproxil fumarate, the orally bioavailable prodrug of tenofovir, is being evaluated in HBV/HIV coinfected patients who developed HBV breakthrough during treatment with lamivudine. [#] ]]>[#] ]]>[#]

Tenofovir gel is packaged in 6-gram tubes and in 4-gram, single-dose applicators. [#] ]]>

Tenofovir has a long intracellular half-life. [#] Serum plasma concentrations with tenofovir gel application have ranged from 3 to 25.8 ng/mL, remaining lower than the 50 ng/mL minimum plasma concentration achieved with oral tenofovir DF. [#]

Animal studies support the use of tenofovir gel as a microbicide. A small study of four rhesus macaques administered intravaginal tenofovir gel, beginning 24 hours before and continuing 48 hours after intravaginal inoculation with simian immunodeficiency virus, resulted in 100% protection, compared with evidence of infection in both of two macaques receiving placebo gel. [#]

HPTN 050, an open-label, Phase I trial, evaluated tenofovir 0.3% and 1% gels, administered daily or twice daily for 2 weeks in sexually abstinent HIV-infected and HIV-uninfected women to determine toxicity, pharmacokinetics, and gel acceptability. Fourteen of 25 women (56%) experienced low but detectable serum tenofovir levels. Asymptomatic bacterial vaginosis in 29 women resolved in 14 (48%) after gel administration. No new resistance mutations evolved, and no patients had high-level tenofovir mutations, such as K65R. [#] [#] Results from the HPTN 050 study have shown tenofovir gel to be generally safe and acceptable. [#]

HPTN 059 a multicenter, randomized, controlled Phase II trial involving HIV-uninfected women, determined the safety and acceptability of tenofovir 1% gel administered over 24 weeks, with a 48-week follow-up. Patients were assigned to one of four cohorts: tenofovir 1% daily; placebo daily; tenofovir 1%, coitally dependent; or placebo, coitally dependent. Primary outcome measures included macroscopic evidence of damage to the cervical, vulvar, or vaginal epithelium, severe erythema, or severe edema, related or not related to the study gel or applicator. [#] Results of the study have yet to be published.

MTN- 001 and MTN-002 are two tenofovir gel pharmacokinetic studies currently in the recruitment stage. MTN-001 is a randomized, open-label, crossover, Phase II trial evaluating the adherence and acceptability of tenofovir gel in a study population. MTN-001 will employ three regimens for comparative purposes, including the use of oral tenofovir dispoproxil fumarate. Primary outcome measures will include self-reported adherence to each regimen, proportion of participants who indicate they would be unlikely to use study product in the future, area under the concentration-time curve (AUC), maximum serum concentrations (Cmax), and minimum serum concentrations (Cmin). [#] MTN-002 is a non-randomized, open-label, cross-over Phase I trial which will assess term pregnancy single-dose pharmacokinetics (PK) of tenofovir 1% gel in HIV uninfected pregnant women. Primary outcome measures will include maternal third trimester pharmacokinetic measures (AUC and Cmax), endometrial tenofovir levels, and placental transfer (cord blood tenofovir levels, placental tissue tenofovir levels, and amniotic fluid tenofovir levels). [#]

MTN-003 is a Phase IIb, safety and effectiveness study exploring tenofovir 1% gel. It is designed to determine the safety and effectiveness of daily tenofovir 1% gel as compared to a vaginal placebo gel, and the safety and effectiveness of oral tenofovir disoproxil fumarate, and oral FTC/TDF compared to an oral placebo preventing HIV infection among women at risk for sexually transmitted infections. MTN-003 is not yet open to participants. [#]

TFV 010 is a randomized, double-blind, placebo-controlled Phase I study of tenofovir gel, which is currently in development and not yet open for participant recruitment. The purpose of the study is to assess whether there is a measurable response to daily vaginal applications of 1% tenofovir gel in women at low risk for HIV infection. TFV 010 will measure the mucosal response to daily intravaginal applications of 1% tenofovir gel versus placebo in two groups of women. Primary outcomes measures are changes in cytokines, chemokines, and other mediators of innate immunity. [#] ]]>

The most common adverse effects noted were itching (23%), redness (18%), discharge (15%), irregular menstruation (13%), and uterine bleeding (11%). Vaginal candidiasis occurred in 5% of women while using the gel. [#]

In irritation studies, tenofovir 0.3% and 1% gels, adjusted to pH 4 to 5, appear nearly equal to carrier vehicles in irritation scores. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>Tenofovir gel studied. AIDS Patient Care STDS. 2002 Aug;16(8):401-2.
D'Cruz OJ, Uckun FM. Clinical development of microbicides for the prevention of HIV infection. Curr Pharm Des. 2004;10(3):315-36.
Meyer KH, Maslankowski LA, Gai F, El-Sadr WM, Justman J, Kwiecien A, Masse B, Eshleman SH, Hendrix C, Morrow K, Rooney JF, Soto-Torres L; HPTN 050 Protocol Team. Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women. AIDS 2006 Feb 28;20(4):543-551.
HPTN059: Phase II Expanded Safety and Acceptability Study of the Vaginal Microbicide 1% Tenofovir Gel. Available at: Accessed 06/01/09.
Safety and Acceptability of a Vaginal Microbicide. Available at: Accessed 06/01/09.]]>
<![CDATA[UC-781]]>[#] ]]>[#] ]]>[#] [#] ]]>[#] Rectal. [#] ]]>[#] [#] UC-781 has been studied in once-daily dosages for up to 7 days and in twice-daily dosages for up to 14 days. [#] [#] ]]>[#] It is effective against transmission of both free-floating HIV particles and cell-associated HIV. UC-781 has an intracellular antiviral protective effect and a half-life of 5.5 days. [#] [#]

In vitro exposure of human cervical tissue to UC-781 for 30 minutes has resulted in 95% reduction of subsequent HIV infection. Furthermore, greater concentrations of UC-781 pretreatment have resulted in total protection of the cervical tissue from both X4- and R5-tropic HIV-1 isolates as well as from cell-associated HIV-1 infection. Twenty-minute incubation with UC-781 has completely protected the cervical tissue up to 48 hours post-treatment without associated tissue toxicity. [#]

UC-781 administered to cellular and tissue explant models as a 0.1% carbopol gel formulation has demonstrated a potent, dose-dependent effect against R5- and X4-tropic HIV infections in T cells. In human cervical explant cultures, UC-781 was able to not only inhibit direct infection of mucosal tissue but also to prevent dissemination of virus by migratory cells. UC-781 retained significant activity against direct tissue infection and migratory cell infection. UC-781 demonstrated prolonged inhibitory effects able to prevent both localized and disseminated infections up to 6 days post-treatment. In addition, a 2-hour exposure to UC-781 prevented infection of lymphoid tissue when challenged up to 2 days later. Although a greater dose of UC-781 was required to inhibit infections of lymphoid versus cervical explant, that dose, equivalent to a 1:3.000 dilution, was less than the full dose provided in a 0.1% formulation. [#]

The prolonged protective effect of UC-781, characterized as a memory effect that continues to protect drug-treated cells from HIV-1 replication, has been demonstrated for up to 12 days. [#]

UC-781 has been studied with the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine in vitro. A 1:1 molar combination of zidovudine plus UC-781 showed high-level synergy in inhibiting replication of a zidovudine-resistant clinical isolate of HIV. When a 1:1 molar combination of zidovudine and UC-781 was compared to use of either drug alone, HIV resistance development was significantly slower. [#]

The microbicidal activity of UC-781 has been studied in vitro against strains of HIV-1 resistant to UC-781 (UCR), efavirenz (EFVR), and nevirapine (NVPR). UC-781 was 10- to 100-fold less effective against resistant strains than wild-type virus. The drug was more effective against NVPR strains than UCR strains, and was less effective against EFVR strains than UCR strains. Efficacy of UC-781 was dose-dependent; 25 mcM UC-781 provided essentially equivalent microbicidal activity against NNRTI-resistant and wild-type virus. UC-781 formulations under current development contain concentrations approximately 100-fold greater than the 25 mcM concentration necessary for efficacy. [#] ]]>
[#] The combination of UC-781 and another candidate microbicide, cellulose acetate 1,2-benzenedicarboxylate, resulted in effective synergy for inhibition of HIV-1 in vitro and in peripheral blood mononuclear cells. Concomitant administration provided complementary mechanisms of action and protected ex vivo lymphoid tissues from HIV infection. [#] ]]>[#] ]]>[#] ]]>Liu S, Lu H, Neurath AR, Jiang S. Combination of candidate microbicides cellulose acetate 1,2-benzenedicarboxylate and UC-781 has synergistic and complementary effects against human immunodeficiency virus type 1 infection. Antimicrob Agents Chemother. 2005 May;49(5):1830-6.
Patton DL, Sweeney YT, Balkus JE, Rohan LC, Moncla BJ, Parniak MA, Hillier SL. Preclinical safety assessments of UC-781 anti-human immunodeficiency virus topical microbicide formulations. Antimicrob Agents Chemother. 2007 May;51(5):1608-15.
Roth S, Monsour M, Dowland A, Guenthner PC, Hancock K, Ou CY, Dezzutti CS. Effect of topical microbicides on infectious human immunodeficiency virus type 1 binding to epithelial cells. Antimicrob Agents Chemother. 2007 Jun;51(6):1972-8.
Sassi AB, Isaacs CE, Moncla BJ, Gupta P, Hillier SL, Rohan LC. Effects of physiological fluids on physical-chemical characteristics and activity of topical vaginal microbicide products. J Pharm Sci. 2007 Oct 5 [Epub ahead of print].
Van Herrewege Y, Michiels J, Van Roey J, Fransen K, Kestens L, Balzarini J, Lewi P, Vanham G, Janssen P. In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides. Antimicrob Agents Chemother. 2004 Jan;48(1):337-9. Phase I Study of Safety and Persistence of UC-781 Vaginal Microbicide. Available at: Accessed 02/12/08.]]>
Suite 200
South San Francisco, CA 94080
Phone: 650-616-2200]]>
<![CDATA[Apricitabine]]>[#] [#] ]]>[#] [#] ]]>[#] [#] ]]>[#] ]]>[#] Apricitabine has been studied at doses of 200, 400, 600, and 800 mg twice daily and at doses of 800, 1,200, and 1,600 mg once daily. [#] [#] No apparent differences have been seen between daily and twice daily dosing schedules. The twice daily dosing schedule provides adequate and sustained intracellular accumulation and has been chosen as the primary schedule for continued study; once daily dosing may be determined in later trials. [#] ]]>[#] [#] [#]

Apricitabine must be metabolized intracellularly to its triphosphate form, apricitabine-TP, to exhibit antiviral activity. Intracellular concentrations of the active triphosphate are proportional to plasma concentrations of apricitabine. Apricitabine-TP accumulates intracellularly with twice-daily dosing, has a half-life of 6 to 7 hours, and achieves maximum plasma concentrations (Cmax) at approximately 4 hours post dose. [#] In Phase I studies, oral bioavailability of AVX754 was 65% to 80% with 1,600 mg to 400 mg single doses, respectively. Apricitabine is rapidly absorbed. [#] The time to Cmax ranged from 1.5 to 1.7 hours and was unaffected by dose or gender. Plasma protein binding of apricitabine is less than 4%. [#] The drug appears to penetrate the cerebrospinal fluid. Apricitabine exhibits linear pharmacokinetics following administration of single and multiple doses. Apricitabine is renally eliminated by glomerular filtration and active tubular secretion in the kidney. [#] [#] Elimination is unaffected by gender. Most of the parent drug is excreted within the first 8 hours. [#] [#] Apricitabine and its active triphosphate metabolite do not appear to inhibit or induce any of the major cytochrome P (CYP) 450 isozymes, including CYP1A2, 2A6, 2C9, 2D6, and 3A4. [#]

A pharmacokinetic study compared single and multiple doses of apricitabine 800 mg in 39 HIV uninfected and in 18 healthy participants. In addition, pharmacokinetics of the active triphosphate, apricitabine -TP, were compared in 9 HIV infected and 21 healthy participants who received apricitabine 600 mg twice daily for 8 or 4 days, respectively. Pharmacokinetics of apricitabine appear similar in HIV uninfected and healthy groups. After a single 800 mg dose, the maximum plasma concentration (Cmax) was 7.9 mcg/ml in healthy participants and 7.2 mcg/ml in HIV infected participants. The area under the concentration-time curve (AUC) was similar between the groups as well at 44.9 mg h/l and 39.5 mg h/l, respectively. After 8 days of apricitabine 800 mg once daily administration, Cmax was 8.4 mcg/ml and 9.7 mcg/ml in healthy and HIV infected groups, respectively; AUC was 41.8 mg h/l and 38.1 mg h/l, respectively. Apricitabine-TP Cmax after 8 days in HIV infected participants was twofold higher than Cmax observed after 4 days in healthy participants. [#]

In a 10-day study of apricitabine in antiretroviral-naive, HIV infected adults, single apricitabine doses of 400, 800, 1,200, and 1,600 mg were evaluated. Viral load decreased significantly at 1 week across all doses: approximately 90% with 400 mg; nearly 95% with 800 mg; nearly 97% with 1,200 mg; and 95% with 1,600 mg. After 10 days of daily apricitabine treatment, viral load reductions of nearly 98% with 1,200 mg and 1,600 mg were significantly greater than the approximately 90% reduction seen with 400 mg. No CD4 count changes were observed. [#]

A Phase IIb dose-ranging trial in treatment-experienced HIV infected patients is ongoing to determine apricitabine activity in patients with HIV strains resistant to lamivudine and that have the M184V mutation. Responses to doses will be compared to each other and to lamivudine for 21 days and 24 weeks. [#]

Resistance to apricitabine develops slowly compared with other NRTIs such as lamivudine and is associated with the K65R, V75I, and M184V mutations. Apricitabine is active against zidovudine- and lamivudine-resistant viruses. [#] The presence of five thymidine analogue mutations (TAMs) resulted in a less than twofold median change in apricitabine activity. No new resistance-conferring mutations emerged after 10 days of monotherapy; patients with baseline nucleoside analogue mutations showed promising decreases in viral load. [#] ]]>
[#] [#] Apricitabine is not mutagenic. [#] No evidence of mitochondrial toxicity has been observed in vitro at concentrations 30 times greater than Cmax. [#]

In a 10-day, dose-ranging study of apricitabine monotherapy in 63 antiretroviral-naive, HIV infected patients, apricitabine was well tolerated at all doses. No serious adverse events were reported, and no treatment required discontinuation. Headache was the most commonly reported adverse event in patients taking apricitabine (42% of study participants), but headache frequency was similar to that of the placebo group. Nasal congestion appeared slightly more common with apricitabine than with placebo. Myalgia was reported by 10% of patients receiving apricitabine, but the relationship between myalgia and apricitabine is unclear. Low-level lipase changes similar to those in the placebo group and six cases of increased serum lipase that appeared unrelated to apricitabine were reported. Otherwise, no clinically significant laboratory changes were reported. [#] [#] ]]>

Apricitabine displayed additive to synergistic antiviral activity in vitro against wild-type HIV-1 when combined with a range of antiretrovirals. [#] Specifically, apricitabine and lamivudine had additive antiviral activity by sharing a common anabolic pathway. In a Phase I study that combined apricitabine and lamivudine, lamivudine reduced intracellular AVX754-TP concentrations in a dose-dependent manner by four- to sixfold relative to the apricitabine-TP concentration alone. Apricitabine had no effect on lamivudine or lamivudine-triphosphate concentrations. [#] [#]

The effect of trimethoprim on apricitabine excretion was studied in isolated perfused rat kidney because trimethoprim inhibits the excretion of lamivudine, which is structurally similar to apricitabine. Trimethoprim inhibited the excretion of apricitabine and its metabolite BCH-335. Because renal excretion of apricitabine and lamivudine are inhibited by trimethoprim to similar extents, exposure of apricitabine would also be expected to increase in the presence of therapeutic concentrations of trimethoprim. [#]

Because apricitabine does not induce or inhibit any of the major CYP450 isozymes, there is a low potential for interaction with drugs that undergo hepatic CYP metabolism. [#]

A Phase I study in 18 healthy participants compared apricitabine monotherapy versus apricitabine combined with tipranavir. Tipranavir significantly reduces the plasma levels of some NRTIs, such as zidovudine and abacavir. However, no reduction in apricitabine plasma levels occurred with concomitant tipranavir. [#]

Coadministration of lamivudine and apricitabine to HIV infected cells in vitro decreased the conversion of apricitabine to its triphosphate, but apricitabine did not affect lamivudine phosphorylation. [#] ]]>
[#] ]]>[#] ]]>A Phase II, Randomised, Double-Blind, Dose-Ranging Study of AVX754 Versus Lamivudine in Treatment-Experienced HIV-1 Infected Patients With the M184V Mutation in Reverse Transcriptase. Available at: Accessed 04/06/09.
Bethdeel et al. In vitro activity of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI), against 215 HIV-1 isolates resistant to other NRTIs. Antivir Chem Chemother. 2005;16(5):295-302.
Cahn P, Cassetti I, Wood R, Phanuphak P, Shiveley L, Bethell RC, Sawyer J. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients. AIDS 2006;20(9):1261-1268.
Otto MJ. New nucleoside reverse transcriptase inhibitors for the treatment of HIV infections. Curr Opin Pharmacol. 2004 Oct;4(5):431-6.
Tomoko Nakatani-Freshwater, Mariana Babayeva, Aruna Dontabhaktuni, and David R. Taft Effects of Trimethoprim on the Clearance of Apricitabine, a Deoxycytidine Analog Reverse Transcriptase Inhibitor, and Lamivudine in the Isolated Perfused Rat Kidney. J. Pharmacol. Exp. Ther. 2006;319: 941-947.]]>
Richmond Victoria,
<![CDATA[Elvucitabine]]>[#] [#] ]]>[#] [#] ]]>[#] ]]>[#] [#] ]]>[#] ]]>[#] [#] ]]>[#] Pharmacokinetic modeling suggests that elvucitabine maintains potent antiretroviral activity, even at doses low enough to avoid bone marrow toxicity. [#] [#] Elvucitabine inhibits wild-type HIV and HIV expressing the M184V mutation associated with lamivudine resistance. [#]

Elvucitabine has excellent oral bioavailability and a prolonged plasma half-life of greater than 100 hours. Early-stage clinical results suggest that elvucitabine's steady-state occurs following 21 days of dosing. [#] [#] [#]

In a 21-day study of 24 HIV-infected patients receiving elvucitabine at dosages of 5 or 10 mg once daily, or 20 mg every 48 hours with concomitant lopinavir/ritonavir (LPV/r) every 12 hours, viral load, compared to baseline, decreased 1.8, 1.9, and 2.0 log, respectively. Due to elvucitabine's extended half-life, LPV/r was continued to day 35 in the 10 and 20 mg cohorts. Concentrations of elvucitabine remained above the 50% inhibitory concentration (IC50) at Day 28, supporting weekly or twice-weekly dosing. The 20 mg every 48 hours cohort appeared most efficacious and minimized resistance and adherence concerns. [#]

Results from the 48-week treatment segment of a randomized, double-blind phase II trial of elvucitabine in combination with two additional antiretrovirals, efavirenz and tenofovir,as compared to lamivudine (3TC) in combination with the same two additional antiretrovirals, demonstrated elvucitabine antiviral potency to be similar to 3TC. In the elvucitabine-treated group, 96% of patients reached undetectable viral load, defined as achieving fewer than 50 copies/mL after 48 weeks of therapy. [#] ]]>
[#] [#]

In the 21-day trial of 24 HIV-infected patients receiving elvucitabine 5 or 10 mg once daily or 20 mg every 48 hours, bone marrow suppression was not observed, and elvucitabine was determined to be generally nontoxic. [#] Data at 48 weeks from the trial comparing elvucitabine in combination with two additional antiretrovirals versus 3TC in combination with the same two antiretrovirals, demonstrated that elvucitabine was well-tolerated and displayed a safety profile similar to 3TC for both incidence and severity of adverse events. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>Chen, SH. Comparative evaluation of L-Fd4C and related nucleoside analogs as promising antiviral agents. Curr Med Chem. 2002 May;9(9):899-912.
Dutschman GE, Grill SP, Gullen EA, Haraguchi K, Takeda S, Tanaka H, Baba M, Cheng YC. Novel 4'-substituted stavudine analog with improved anti-human immunodeficiency virus activity and decreased cytotoxicity. Antimicrob Agents Chemother. 2004 May;48(5):1640-6.
Patel J, Mitra AK. ACH-126443 Achillion/Yale University. Curr Opin Investig Drugs. 2002 Nov;3(11):1580-4. Review.
Study of Once Daily Elvucitabine Versus Lamivudine in Subjects With a Documented M184V Mutation (Resistance). Available at: Accessed 04/05/09.]]>
New Haven, CT 06511
Phone:  203-624-7000]]>
<![CDATA[Fosalvudine]]>[#] ]]>[#] ]]>[#] [#] ]]>[#] ]]>[#] [#] ]]>[#] [#]

In vitro, fosalvudine inhibits the replication of HIV group M subtypes A through G. In a murine tissue study, low concentrations of fosalvudine were distributed to fat and bone marrow, which suggests a low potential for hematopoetic toxicity. [#]

Fosalvudine is being studied in Phase II trials in treatment-naïve and treatment-experienced patients infected with HIV-1. In a 14-day, dose-finding, Phase II study in treatment-naïve patients, fosalvudine exhibited dose-dependent efficacy across 10- to 40-mg doses. Mean viral load reduction at day 15 was 60% for the 5-mg dose, nearly 80% for the 10-mg dose, 85% for the 20-mg dose, and 90% for the 40-mg dose compared with placebo (nearly 0% change in viral load). Fosalvudine is currently being studied in a Phase II trial in treatment-experienced patients. [#] ]]>
[#] ]]>CahnP., et al. A phase-II study of 14 days monotherapy with the nucleoside-analogue Fosalvudine Tidoxil in treatment-naïve HIV-1 infected adults. Poster exhibition: 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention: Abstract no. WEPEB114LB. Available at: Accessed 09/08/08.]]>D-68526 Ladenburg
<![CDATA[KP-1461]]>[#] [#] [#] ]]>[#] [#] [#] ]]>[#] [#] ]]>[#] ]]>[#] KP-1461 introduces continual mutations into the HIV genome during viral replication by reverse transcriptase (RT). These mutations decrease virus viability and lead to viral collapse. This mechanism, selective viral mutagenesis or lethal mutagenesis, is novel to the nucleoside analogue class. [#]

Unlike approved nucleoside RT inhibitors (NRTIs) that contain a modified sugar and an unmodified base, KP-1461 contains a natural or unmodified sugar and a modified base, allowing for efficient recognition by the viral polymerase and multiple base pairing. Because KP-1461 pairs with multiple bases, it is able to target all viral proteins rather than a single protein. [#] [#]

KP-1461, after conversion to KP-1212, is metabolized to a triphosphate and incorporated into the HIV-1 genome by RT. The drug is similarly incorporated into human mitochondrial DNA polymerase. [#] The active substance, KP-1212, has been shown to inhibit viral activity in tissues after just one pass; accumulation has been shown to eradicate the virus entirely. [#] It has also been found that HIV strains treated with KP-1212 demonstrate increased sensitivity to zidovudine. [#]

KP-1461 has been evaluated in a Phase Ib, randomized, double-blinded, placebo-controlled safety and pharmacology trial. In this trial, approximately 40 HIV-infected subjects failing prior antiretroviral therapy received escalating doses of KP-1461 or placebo in four cohorts. KP-1461 also entered a Phase IIa, open-label trial evaluating safety, efficacy, and tolerability as a monotherapy in 32 treatment-experienced, HIV infected subjects. [#] [#] However, in order to investigate data discrepancy and examine clinical results, this trial was suspended by the drug developers. [#]

In laboratory tests, multiple tissue passes in the prescence of SN1212 failed to induce resistant HIV isolates after several attempts. In addition, cross resistance to SN1212 has not been observed with HIV strains resistant to common nucleoside analogues such as zidovudine, lamivudine, stavudine, and abacavir. [#] [#] ]]>
[#] At doses up to 2 g/kg, no toxicity was observed in dogs; lactate levels did not increase, reflecting a lack of mitochondrial toxicity. [#] KP-1461 appears safe and well-tolerated in humans, with no dose-related toxicities observed in Phase I studies. [#] [#] Results from the suspended Phase IIa open-label trial suggest occasional mild to moderate adverse events related to the use of KP-1461. [#] ]]>Novel anti-HIV agent enters Phase IIa clinical trial. Expert Rev Anti Infect Ther. 2007 Aug;5(4):540-1.
Harris KS, Brabant W, Styrchak S, Gall A, Daifuku R. KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. Antiviral Res. 2005 Jul;67(1):1-9. PMID: 15890415
Harris K, Brabant B, Li L, Styrchak S, Gall A, Daifuku R. SN1212/1461 a Novel Mutagenic Deoxyribonucleoside Analog with Activity Against HIV. San Francisco, Abstract 532, 2004.
ClinicalTrials.Gov - Safety and Efficacy Study of KP-1461 to Treat ART-Experienced HIV+ Patients. Available at: Accessed 04/08/09. ]]>
Redmond, WA 98052
Phone: 425-825-0240
Fax: 425-825-7470]]>
<![CDATA[Racivir]]>[#] Racivir is a 50:50 mixture of emtricitabine and its positive enantiomer. [#] ]]>[#] Racivir is a 50:50 mixture of emtricitabine and its positive enantiomer. [#] ]]>[#] [#] Racivir has been compared to lamivudine, an approved cytosine analog, in clinical trials as part of a triple-agent regimen with stavudine and efavirenz. Racivir is now being studied in phase II/III clinical trials as part of combination therapy for the treatment of HIV-1 infection. [#] [#] ]]>[#] [#] ]]>[#] ]]>[#] [#] Clinical trials have evaluated racivir dosages of 200, 400, and 600 mg once daily for up to 14 days. [#] ]]>[#]

In a Phase I/II dosing study, racivir was administered to HIV infected, treatment-naive, male volunteers in combination with stavudine and efavirenz for 14 days. Racivir was administered once daily at doses of 200, 400, or 600 mg. The combination regimens resulted in a rapid initial drop in viral load, with mean 10-fold reductions by Day 4. Mean HIV RNA levels continued to drop, though more slowly, through the end of treatment on Day 14, resulting in a greater than 20-fold reduction in viral load. Upon cessation of therapy, HIV RNA levels remained suppressed from all doses for more than 2 weeks. Viral load remained steady through Day 28. By Day 35, HIV RNA levels began to increase but still remained at least 10-fold less than baseline levels. [#] [#]

Racivir displays excellent oral bioavailability in human preclinical studies. [#] In a Phase I/II study of racivir in treatment-naive men, pharmacokinetic parameters were dose proportional across 200, 400, and 600 mg dose levels. [#]

A Phase II, randomized, double-blind, placebo-controlled study was conducted to assess the safety, tolerability, and antiviral effect of a racivir 600 mg dose compared with lamivudine in HIV infected, treatment-experienced participants with the M184V mutation who have been on lamivudine as part of a combination regimen. One group of 16 participants continued on existing therapy with lamivudine, and the second group of 26 participants received racivir in place of lamivudine in existing regimens. Participants received 28 days of blinded therapy followed by 20 weeks of open-label treatment. After 28 days of blinded treatment, the mean viral load rose by 34.9% in the lamivudine group and dropped by 60.2% in the racivir group (p=0.02). A subset analysis of 14 participants in the racivir-treated group revealed that the change in viral load was largely due to a positive antiviral response in participants who had an HIV mutation pattern that included M184V and less than three thymidine analog mutations with or without non-nucleoside reverse transcriptase inhibitor or protease inhibitor mutations. Replacing lamivudine with racivir in their existing therapies caused a mean drop in viral load of 80% (p=0.004) in the second week of treatment. [#] [#]

Racivir has demonstrated antiviral activity in patients harboring HIV with the lamivudine-associated M184V mutation and with less than three thymidine-associated mutations. Because such mutations are consistent with first-line therapy failure, racivir may be useful as part of a combination second-line treatment regimen. [#] ]]>
[#] In a 14-day, Phase I/II study conducted in HIV infected men, racivir 200, 400 and 600 mg doses were well tolerated in combination with stavudine and efavirenz. [#]

In an ongoing Phase II trial of 42 HIV infected patients comparing racivir to lamivudine as part of a combination regimen, no severe adverse effects attributed to therapy were noted over the 28 days. As open-label dosing of racivir continues in this trial, safety data will be presented. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>Herzmann C, Arasteh K, Murphy RL, Schulbin H, Kreckel P, Drauz D, Schinazi RF, Beard A, Cartee L, Otto MJ. Safety, pharmacokinetics, and efficacy of (+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine with efavirenz and stavudine in antiretroviral-naive human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2005 Jul;49(7):2828-33.
Otto MJ. New nucleoside reverse transcriptase inhibitors for the treatment of HIV infections. Curr Opin Pharmacol. 2004 Oct;4(5):431-6.
Study Comparing Racivir and Lamivudine in Treatment-Experienced HIV Subjects. Available at: Accessed 05/18/07.]]>
1860 Montreal Road
Tucker, GA 30084
Phone: 678-395-0035]]>
<![CDATA[Bevirimat]]>[#] [#] [#] ]]>[#] [#] [#] ]]>[#] ]]>[#] ]]>[#] [#] [#]

Both bevirimat 100 and 200 mg oral solutions have been studied in a Phase IIa trial, and a bevirimat 50 mg tablet to be used for 400 mg daily dosing has been studied in a Phase IIb trial. Early clinical bioavailability studies indicated that the tablet had approximately 60% of the oral bioavailability of an oral solution formulation. Thus, plasma concentrations after administration of a single 400 mg dose of bevirimat were expected to be comparable to those after administration of the bevirimat 200 mg oral solution. However, plasma concentrations with bevirimat 400 mg tablet dosing were actually about half what was expected and were more similar to concentrations achieved with bevirimat 100 mg oral solution dosing. Data suggest that the lower plasma concentrations result from properties of the bevirimat 50 mg tablet used in the Phase IIb trial. [#] Phase IIb studies are continuing but are using bevirimat oral liquid formulation in increasing dose cohorts. [#] In addition, the manufacturer is considering a tablet formulation for use in a planned Phase III trial. [#] ]]>
[#] [#] SP1 is a small spacer peptide separating the CA and NC domains in the Gag polyprotein precursor. Bevirimat is specifically active at the CA-SP1 cleavage site. [#]

Amino acid residues in CA-SP1 Gag domains are critical for drug activity; thus, determinants that confer resistance map to this Gag domain. [#] An adenine (A) to valine (V) change at the first or third residues at the N-terminus of SP1 (A1V or A3V) resulted in a resistant phenotype. [#] However, genetic analysis of available patients showed no development of resistance, and bevirimat retained potency in patients with existing extensive mutations. [#]

Oral bevirimat is rapidly absorbed in animal models and in humans and has a half-life of nearly three days (60.3 hrs). [#] [#] A 10-day, multiple-dose trial in healthy males evaluated daily doses of 25, 50, and 100 mg bevirimat. Peak plasma concentrations (Cmax) at Day 10 were 7.98, 15.58, and 31.58 mcg/ml, respectively. Drug plasma levels accumulated approximately three- to fivefold from baseline. Areas under the concentration-time curve (AUC) at Day 10 were 156.5, 303.1, and 599.5 hr(mcg)/ml, respectively. The target minimum therapeutic concentration (Cmin) of bevirimat was determined to be 2.3 mcg/ml and was achieved with single daily doses of 25 mg; tenfold target Cmin concentrations were safely achieved with single daily doses of 100 mg. [#] Bevirimat demonstrated dose-related antiviral activity in a single-dose pharmacokinetic and -dynamic model and in a multiple-dose evaluation. [#] [#]

Bevirimat was nonteratogenic when administered orally in rats and rabbits. No developmental toxicity was observed up to the highest tested dosages of 900 mg/kg/day in the rat and 300 mg/kg/day in the rabbit. These dosages are approximately 44 and 29 times greater, respectively, than the potential human dosage for bevirimat of 200 mg/day. [#] Bevirimat is not oxidatively metabolized by the cytochrome P 450 (CYP) liver enzyme system. Testing of CYP enzymes 1A2, 2C9, 2C19, 2D6, and 3A4 showed no inhibition in human livers by the drug. Bevirimat is glucuronidated primarily by uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) 1A3 and weakly inhibits glucuronidation by some UGT isoforms. [#] Bevirimat displayed linear clearance in a three-cohort study of single 75, 150, or 250 mg doses. [#]

When tested against a panel of resistant HIV strains, bevirimat retained wild-type activity, whereas approved antiretroviral medications exhibited decreases in activity that ranged from several-fold to more than 100-fold. [#] Viral resistance to bevirimat was also examined in vitro, and five amino acid changes were identified that independently confer resistance: H226Y, L231M, and L231F at the C-terminus of CA; and A1V and A3V at SP1. The A3V/G225S mutant was fully drug resistant. The clustering of bevirimat resistance mutations at the CA/SP1 junction confirms that this region is the major target of bevirimat activity. Drug dependence observed for A3V mutations suggests multiple mechanisms of resistance. Viral resistance was not detected in vivo during a 10-day, multi-dose study that used standard genotyping methods. [#] Further resistance studies conducted in vitro have confirmed that mutations that confer resistance to bevirimat are found only at or near the site of the drug's mechanism of action: the capsid-SP1 cleavage site in the HIV Gag protein. The six in vitro mutations that induce resistance are CA-H226Y, L231M, and L231F, and SP1-A1V, A3V, and A3T. Bevirimat resistance may develop in the presence of pre-existing protease inhibitor mutations; however, a recent study suggests that PI-resistant mutants may be less likely than wild-type isolates to develop PA-457 resistance. [#] [#]

Genetic polymorphism in the Gag region of HIV resulted in viral resistance to bevirimat in a Phase II study of 88 HIV-infected patients. The polymorphism occurs in approximately 40% of clade-B HIV; pretreatment screening for the polymorphism may be necessary to identify patients who will respond to treatment with bevirimat. [#]

In a Phase I dose-evaluation trial, twenty-four healthy men received a single oral dose of bevirimat 25, 50, 100, or 250 mg. In each group, six men received active drug, and two men received placebo. Doses of bevirimat 50 mg or greater exceeded target plasma concentrations for more than 24 hours, establishing the possibility of once-daily therapeutic dosing. [#]

A single-dose, double-blind, placebo-controlled trial in twenty-four HIV infected patients with CD4 counts of 200 cells/ml or greater and viral loads of 5,000 to 250,000 copies/ml compared 75, 150, and 250 mg doses of bevirimat to placebo. All groups showed sustained decreases in viral load after 10 days. Viral load decreases appeared dose-dependent: approximately 70% reduction was achieved with bevirimat 250 mg; nearly 60% reduction with bevirimat 150 mg; and nearly 50% reduction with bevirimat 75 mg. [#]

A Phase IIa, double-blind, placebo-controlled trial examined daily doses of bevirimat 25, 50, 100, or 200 mg in HIV infected patients who were treatment-naive for at least 12 weeks prior to the trial. Six patients received active drug in each dose group, and eight patients received placebo; all groups were treated for 10 days. The primary endpoint of demonstrated antiviral activity was evaluated on Day 11. Steady-state plasma concentrations were reached after approximately seven days of therapy. Bevirimat displayed dose-proportional pharmacokinetics: the 200 mg dose achieved a minimum serum concentration double that of the 100 mg dose. After a mild initial increase, viral load decreased significantly in the 100 and 200 mg dose groups compared with placebo. Day 11 median reductions were nearly threefold and approximately tenfold, respectively. In patients whose baseline viral loads were less than 100,000 copies/ml, median reductions with 100 and 200 mg doses were approximately threefold and 33-fold, respectively. Twenty-one of thirty-three patients showed no resistance to bevirimat. [#] [#]

In a Phase II, dose-finding study of bevirimat in 88 HIV-infected patients, only some patients responded to monotherapy treatment. Patients with adequate trough concentrations experienced maximal viral load decrease of approximately 20-fold after 7 days. [#]

A Phase IIb study was initiated in 2006 to study bevirimat in HIV infected patients who were failing current antiretroviral therapy. The primary endpoints included reduction in viral load after 14 days and after 3 months. In the first cohort, patients were administered bevirimat or placebo once daily for 3 months in combination with background antiretroviral therapy. A second, dose-escalation, cohort planned to enroll 12 treatment patients plus four placebo patients in three bevirimat once-daily dosage groups: 400, 500, and 600 mg. [#] Results from the first cohort showed an antiviral effect of bevirimat after 14 days of 400 mg daily dosing. At Day 15, the mean viral load reduction was approximately 60% in patients treated with 400 mg bevirimat. Two of 12 patients with drug-resistant HIV and treated with bevirimat achieved undetectable virus levels (HIV viral load less than 400 copies/ml), and one additional patient achieved viral load reduction of more than 90%. The overall plasma concentrations, and thus antiviral response, in the first cohort of bevirimat 400 mg was lower than expected, based on earlier bioavailability studies predicting concentrations similar to those seen in the Phase IIa study that used bevirimat oral liquid formulation. Data suggest the lower plasma concentrations resulted from the tablet formulation properties. [#] In March 2007, the manufacturer received FDA approval to continue revised dose-escalation cohorts in this study with the oral liquid formulation of bevirimat. In the first cohort, patients are being administered 14 days of bevirimat 250 mg monotherapy (eight patients) or placebo (two patients) once daily in the first cohort; primary endpoints are safety and efficacy (i.e., viral load reduction) of bevirimat at Day 15. Dose escalations of 50 mg are ongoing after completion of the first cohort. [#] In the 250 mg cohort, addition of bevirimat to failing background regimens reduced viral load by mean 0.68log on Day 15 and by .5log or greater in 71% of patients. Efficacy as measured by viral load reduction was greater than with the 400 mg tablet cohort, which had a mean viral load reduction of .036log. Mean steady state plasma concentrations were greater than those seen in earlier studies with the liquid formulation and were approximately double those seen with the tablet formulation of bevirimat 400 mg. [#] A 300 mg cohort was initiated, and eight patients received bevirimat. Mean viral load reduction was greater than in the 250 mg cohort at 1.02log; 75% of patients had greater than 0.5log and 63% had greater than 1log reduction on Day 15. [#] A bevirimat 350 mg cohort was initiated, in which nine patients received bevirimat and two received placebo. On Day 15, mean viral load was reduced 0.62log; 33% had greater than .5log reduction and were all greater than 1log. The area under the concentration-time curve and the steady state mean trough levels were similar in the 300 mg and 350 mg cohorts. The manufacturer intends to continue this Phase IIb trial with a 400 mg cohort. [#] ]]>
[#] [#] Two patients experienced mild adverse effects in the 300 mg cohort of an ongoing Phase IIb trial; bevirimat oral liquid formulation was well tolerated in both the 300 mg and 350 mg cohorts. [#] [#] ]]>[#]

When tested with representative reverse transcriptase, protease, and fusion inhibitors, bevirimat exhibited nearly additive to strongly synergistic activity with each at 90% inhibitory concentrations against a panel of resistant viral strains. [#]

Because both bevirimat and atazanavir interact with the liver's UGT enzymes---bevirimat as a UGT substrate and weak inhibitor and atazanavir as an inhibitor---the combination was studied to determine possible pharmacokinetic interactions. Bevirimat and atazanavir serum concentrations appeared unaffected by concomitant administration, and bevirimat did not increase the hyperbilirubinemia that occurs with atazanavir because of its effect on the UGT system. [#] ]]>
[#] ]]>Adamson CS; Ablan SD; Boeras I; Goila-Gaur R; Soheilian F; Nagashima K; Li F; Salzwedel K; Sakalian M; Wild CT; Freed EO. In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). J Virol. 2006; 80(22):10957-71.
Allaway GP. Development of Bevirimat (PA-457): first-in-class HIV maturation inhibitor. Retrovirology. 2006; 3 Suppl 1:S8.
Temesgen Z; Feinberg JE. Drug evaluation: bevirimat--HIV Gag protein and viral maturation inhibitor. Curr Opin Investig Drugs. 2006; 7(8):759-65.
Wen Z; Martin DE; Bullock P; Lee KH; Smith PC. Glucuronidation of Anti-HIV Drug Candidate Bevirimat: Identification of Human UDP-glucuronosyltransferases and Species Differences. Drug Metab Dispos. 2007; 35(3):440-8.]]>
134 Coolidge Avenue
Watertown, MA 02472
Phone: 617-926-1551
Fax: 617-923-2245]]>
<![CDATA[Cobicistat]]>[#][#]]]>[#][#]]]>[#] Cobicistat is being studied as part of an integrase-based fixed-dose regimen. In addition, cobicistat’s stand-alone role in boosting currently available HIV protease inhibitors is being examined. [#]

Two Phase III clinical trials evaluating a fixed-dose, single-tablet “Quad” regimen of elvitegravir (EVG), an investigational integrase inhibitor; cobicistat; emtricitabine (FTC); and tenofovir disoproxil fumarate (TDF) have been initiated. [#][#][#] A separate Phase III study investigating the safety and efficacy of GS-9350-boosted atazanavir (ATV) versus ritonavir (RTV)-boosted ATV, each administered with FTC/TDF (Truvada), is under way. [#]
]]>[#]]]>GS-9350 has been studied as a tablet in doses of 50, 100, 150, and 200 mg. [#]

GS-9350 is also being studied as part of a single tablet containing EVG 150 mg, cobicistat 150 mg, FTC 200 mg, and TDF 300 mg. [#]

Cobicistat is currently being evaluated in treatment-naïve adults in two Phase III trials as part of a once-daily “Quad” tablet, administered by mouth. [#][#]

A separate Phase III trial of treatment-naïve adults is evaluating GS-9350 150 mg-boosted ATV 300 mg + FTC 200 mg/TDF 300 mg, administered by mouth. [#]

In vitro, preclinical data showed that GS-9350 has no antiviral activity at concentrations up to 90 microM. [#][#][#]

A Phase I study evaluating the safety, tolerability, pharmacokinetics and boosting capacity of GS-9350 compared to RTV found that GS-9350 is a potent (Ki<1 microM) human CYP3A inhibitor; two-step enzyme inactivation studies found that GS-9350 was a potent mechanism-based human CYP3A inhibitor (kinact 0.44 min-1, Ki 0.94 microM). GS-9350 did not activate the human aryl hydrocarbon receptor and was a weak agonist (median effective concentration [EC50]>30 microM) of the human pregnane X receptor, which is responsible for induction of drug metabolism and transport.  In humans, GS-9350 exhibited non-linear pharmacokinetics with respect to dose and time. GS-9350 doses of 100 mg and 200 mg inhibited the clearance of midazolam, the CYP3A probe substrate, by 92% and 95%, respectively, similar in effect to RTV 100 mg. [#][#][#]

Furthermore, GS-9350 showed no inhibition of lipid accumulation in adipocytes at 30 microM and <10% inhibition of insulin-stimulated glucose uptake at 10 microM. [#][#]

Pharmacokinetics data from a Phase I trial of 42 HIV-uninfected volunteers receiving ATV 300 mg coadministered with either GS-9350 100 mg, GS-9350 150 mg, or RTV 100 mg for three 10-day periods with a 4-day washout between each period demonstrate that ATV levels were bioequivalent in participants receiving RTV 100 mg and GS-9350 150 mg. The ATV area under the plasma concentration-time curve for a dosing-interval (AUCtau), peak plasma concentration (Cmax), time to maximum concentration (Tmax) and half-life (T 1/2) were 55,200, 45,100, and 55,900 ng(h)/mL; 5270, 4420, and 4880 ng/mL; 3.0, 3.5, and 3.0 h; and 15.7, 9.7, and 16.7 h for ritonavir 100 mg, GS-9350 100 mg, and GS-9350 150 mg, respectively. [#][#]

A Phase I open-label, partially randomized study evaluating two versions of a fixed-dose single tablet regimen containing either COBI 100 mg or COBI 150 mg, each with EVG, FTC, and TDF versus RTV 100 mg-boosted EVG, FTC/TDF found that the 150-mg GS-9350 dose resulted in maintenance of targeted high EVG trough concentrations (Ctau) based on RTV boosting. Additionally, the fixed-dose combination tablet containing GS-9350 150 mg resulted in clinically equivalent tenofovir and FTC exposures compared to FTC/TDF administered individually. Relative to RTV-boosted EVG, the geometric least-squares means ratios (GMR) (90% confidence interval [CI]) for EVG AUCtau, Cmax, and trough concentration (Ctau) were 118 (110 to 126), 108 (100 to 116), and 110 (95.3 to 127), respectively, with EVG/COBI 150mg/FTC/TDF. Relative to FTC + TDF, FTC GMR (90% CI) were 127 (115 to 140) for AUCtau, 121 (107 to 137) for Cmax, and 126 (118 to 136) for Ctau; TDF GMR (90% CI) were 118 (114 to 122) for AUCtau, 130 (122 to 138) for Cmax, and 124 (119 to 129) for Ctau, with EVG/COBI 150 mg/FTC/TDF. [#][#]

Study 236-0104, an ongoing double-blind, randomized, active-controlled Phase II trial evaluating the safety and efficacy of a fixed-dose single-tablet “Quad” regimen (EVG/GS-9350/FTC/TDF) (n = 48) versus efavirenz/FTC/TDF (Atripla) (n = 23) among HIV-infected treatment-naïve adults, demonstrated that, at 24 weeks, 90% of patients in the “Quad” arm and 83% of patients in the Atripla arm achieved viral load <50 copies/mL. At 24 weeks, patients in the “Quad” arm experienced a median increase in CD4 cell count of 123 cells/mm3, compared to a median increase of 124 cells/mm3 in the Atripla arm. At Week 48, 90% patients in the “Quad” arm and 83% of patients in the Atripla arm achieved the study’s primary objective of HIV-1 RNA levels of less than 50 copies/mL, using an analysis where missing equals failure. When using an analysis where missing values were excluded, 96% and 95% of patients in the “Quad” and Atripla groups, respectively, achieved HIV-1 RNA levels of less than 50 copies/mL. Patients taking the “Quad” versus patients taking Atripla experienced a mean increase in CD4 cell counts of 240 cells/mm3 compared to 162 cells/mm3, respectively, at 48 weeks. [#][#][#][#]

A separate Phase II trial, study 216-0105, is an ongoing double-blind, randomized, active-controlled trial examining the safety and efficacy of cobicistat-boosted ATV (n = 50) compared to RTV-boosted ATV (n = 29), each in combination with FTC/TDF, in HIV-infected treatment naïve adults. Data at 24 weeks found that 84% of patients in the cobicistat group and 86% of those in the RTV-boosted ATV group achieved viral load <50 copies/mL, the primary outcome measure.  Patients taking a cobicistat-boosted regimen experienced a median increase in CD4 cell count of 206 cells/mm3, compared with 190 cells/mm3 among patients in the RTV-boosted group. At 48 weeks, 82% and 86% of patients in the cobicistat and ritonavir groups, respectively, met the primary objective of achieving HIV RNA levels of less than 50 copies/mL, using an analysis where missing equals failure. When using an analysis where missing values are excluded, 91% of patients in the cobicistat arm and 96% of those in the ritonavir arm achieved HIV RNA levels of less than 50 copies/mL. In addition, at Week 48, patients taking a cobicistat-boosted regimen experienced a mean increase in CD4 cell count of 230 cells/mm3, compared to a mean increase of 206 cells/mm3 among patients taking a ritonavir-boosted regimen. [#][#][#][#]
In a Phase I crossover trial (n = 42) comparing ATV 300 mg with either GS-9350 100 mg, GS-9350 150 mg, or RTV 100 mg, reported adverse events were mild to moderate and resolved on treatment. Three participants taking ATV/GS-9350 (n = 2 at 100 mg, n = 1 at 150 mg) discontinued treatment due to skin rash. Neither Grade 3/4 laboratory abnormalities nor serious adverse events, including liver toxicity or clinically relevant heart rhythm (ECG) changes, were seen. [#][#]

In a separate Phase I 14-day multiple-dose escalation study, one drug-related Grade 3 adverse event (discoordination) occurred in a single trial participant during multiple dose administration of GS-9350 100 mg.  No participants developed drug-related Grade 3/4 laboratory abnormalities or Grade 4 adverse events. [#][#]

Safety data from study 236-0104 demonstrated a similar discontinuation rate and adverse event profile for both arms of the trial. Three patients discontinued treatment in each arm of the study. In the “Quad” group, no patients discontinued due to an adverse event, compared to one subject who stopped treatment in the Atripla group. Adverse event rates were reported as similar between treatment arms, although fewer CNS events were observed among “Quad” patients. The most commonly observed treatment-emergent adverse events occurring in greater than 5% of patients in either treatment arm were abnormal dreams/nightmares, fatigue, dizziness, diarrhea, somnolence, headache, anxiety, nausea, abdominal distension, and rash. Two Grade 3/4 adverse events were observed among “Quad” patients (pneumonia and anogenital warts); two Grade 3/4 adverse events were reported among Atripla patients (B-cell lymphoma with lymphadenopathy and neutropenia). There was a similar incidence of laboratory abnormalities (Grades 2–4) across both arms of the study. Laboratory abnormalities occurring in greater than 5% of patients in either treatment arm included hyperamylasemia, hypercholesterolemia, creatine kinase, neutropenia, and proteinuria. Mean changes in cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides were reported as small and similar in both arms of the study.  [#][#][#]

In study 216-0105, discontinuation rates were similar between the cobicistat and RTV arms. Two cobicistat patients discontinued treatment due to adverse events (vomiting and rash), as did one RTV patient (scleral icterus). The most commonly observed treatment-emergent adverse events occurring in greater than 5% of patients in either treatment arm were diarrhea, nausea, fatigue, and flatulence. There were two Grade 3/4 adverse events among cobicistat-treated patients ( hyperbilirubinemia and rash). The incidence of laboratory abnormalities (Grades 2–4) was similar across both arms. Grades 2–4 laboratory abnormalities occurring in greater than 5% of patients in either treatment arm included hyperbilirubinemia, hyperamylasemia, hypercholesterolemia, creatine kinase, hypophosphotemia and hematuria. Mean changes in cholesterol, LDL, HDL, and triglycerides were reported as similar in both treatment arms.  [#][#][#]

In both study 236-0104 and 216-0105, small increases in serum creatinine with resulting decreases in estimated creatinine clearance (by Cockroft-Gault) were observed by Week 24. In study 236-0104, participants receiving GS-9350 experienced a slightly greater increase in serum creatinine (+0.14 mg/dL vs. +0.04 mg/dL in the Atripla arm). At 24 weeks, mean estimated glomerular filtration (eGFR) rate was lower in the “Quad” arm compared with the Atripla arm (111 vs. 126 mL/min, respectively). In study 216-0105, at Week 24, serum creatinine was slightly elevated in patients taking cobicistat (+0.18 mg/dL) compared with the RTV arm (+0.14 mg/dL). Mean eGFR for patients taking cobicistat and RTV was 102 and 111 mL/min, respectively. Results from a separate renal study in healthy volunteers indicate that cobicistat does not affect actual glomerular filtration rates (GFR) as assessed by iohexol clearance. Reportedly, the increase in serum creatinine with cobicistat occurs within days of drug initiation and is reversible with values returning to baseline within days after cessation of cobicistat. Study investigators also report that in study 216-0105, increases in serum creatinine with resulting decreases in estimated creatinine clearance stabilized through Week 48 and were comparable in both treatment arms. [#][#][#]

[#]]]>[#]]]>Gilead Sciences, Inc. – Newsroom: Press Releases. Gilead Announces Data Demonstrating Pharmacokinetic Boosting Activity of GS 9350 [press release], February 9, 2009. Available at: Accessed 10/02/2010.

Gilead Sciences, Inc. – Newsroom: Press Releases. Gilead Initiates Phase III Clinical Program Evaluating Single-Tablet, Once-Daily “Quad” Regimen for HIV [press release], April 12, 2010. Available at: Accessed 10/02/2010.

Conf Retroviruses Opportunistic Infect 16th, 2009. Abstract 40.

Foster City, CA 94404
Phone: (650) 574-3000
Fax: (650) 578-9264
<![CDATA[Poly(I)-Poly(C12U)]]>[#] ]]>[#] ]]>[#] [#] Poly(I)-poly(C12U) is also being evaluated for its role in lengthening the duration of structured treatment interruptions (STIs) of HAART therapy. [#] ]]>[#] Poly(I)-poly(C12U) is also being studied for the treatment of hepatitis B and C infection, renal cell carcinoma, and malignant melanoma. Phase III studies evaluating the drug for treatment of chronic fatigue syndrome have recently been completed as well. [#] ]]>[#] ]]>[#] [#] ]]>[#] [#] The drug's cell-mediated immunomodulatory properties produce a delayed hypersensitivity response, which may delay viral rebound during structured treatment interruptions (STIs) of HAART. [#]

STI is based on the premise that immune function may recover in stable HIV infected patients by temporarily withdrawing HAART, allowing viral rebound to stimulate the immune response. However, efforts to date have produced conflicting results. When given during the interruption period, poly(I)-poly(C12U) appears to stabilize patients and allows a longer duration of interrupted therapy. [#]

In a Phase IIb study of poly(I)-poly(C12U) for treatment of HIV during STI, 22 patients with viral loads less than 50 copies/ml and CD4 counts of at least 400 cells/mm3 were randomized to receive poly(I)-poly(C12U) 400 mg IV twice weekly or no treatment during STIs over 64 weeks. STIs continued until the viral load rebounded to at least 5,000 copies/ml for 3 consecutive weeks or 50,000 copies/ml at least once. After 9 months, therapy with poly(I)-poly(C12U) significantly prolonged the duration of STI from a mean 13 weeks without treatment to a mean 27 weeks with the drug. Additionally, the number of CD8 cells significantly increased in patients receiving poly(I)-poly(C12U), destroying additional cells infected with the virus. [#]

During in vitro testing, poly(I)-poly(C12U) was equally active against wild-type HIV and HIV resistant to the following: nevirapine, protease inhibitors, or nucleoside analogue reverse transcriptase inhibitors. [#]

Ampligen 400 mg currently is being studied in AMP 720, an open-label randomized trial, for its use prolonging the structured treatment interruption of existing highly active antiretroviral therapy in HIV infected adults with plasma HIV RNA levels less than 50 copies/ml and CD4 counts of at least 400 cells/mm3. [#] [#] ]]>
[#] [#]

In clinical trials of poly(l)-poly(C12U) for various treatments, a low level of clinical toxicity has been observed. An infusion rate-related mild flushing reaction, at time accompanied by tachycardia, shortness of breath, or anxiety, has occurred in approximately 15% of patients. Other adverse effects noted in trials include diarrhea, itching, rash, hypotension, anemia, elevation of kidney function tests, dizziness, and confusion. Mild flu-like symptoms, such as chills, fever, nausea, vomiting, headache, and fatigue, have also been reported but appear to resolve within several months of treatment initiation. [#] ]]>
[#] In addition, in vitro studies have demonstrated poly(I)-poly(C12U) synergy with the following antiretroviral medications: abacavir, amprenavir, didanosine, efavirenz, indinavir, ritonavir, nelfinavir, stavudine, zalcitabine, and zidovudine. [#] ]]>[#] ]]>[#] ]]>Mismatched double-stranded RNA: polyI:polyC12U. Drugs R D. 2004;5(5):297-304. PMID: 15357629
Safety and Efficacy of Ampligen in the Treatment of HIV Patients Failing HAART. Available at: Accessed 01/08/09.
The Role of Ampligen in Strategic Therapeutic Intervention (STI) of HAART. Available at: Accessed 01/08/09.]]>
1617 JFK Blvd, 6th Floor
Philadelphia, PA 19103
Phone: 215-988-0080
Fax: 215-988-1759]]>
1617 JFK Blvd, 6th Floor
Philadelphia, PA 19103
Phone: 215-988-0080
Fax: 215-988-1759]]>
<![CDATA[Valproic acid]]>[#] [#] ]]>[#] [#] ]]>[#] [#] [#] ]]>[#] Valproic acid has been studied in the treatment of manic episodes associated with bipolar disorder and in migraine headache prophylaxis, although it has not been approved by the FDA for these disorders. [#] ]]>[#]

Intravenous. [#] ]]>

Red-colored syrup containing valproic acid 250 mg as a sodium salt per 5 ml. [#]

Dosages of 500 to 750 mg twice daily have been tested for use in combination with enfuvirtide and as part of certain antiretroviral regimens. [#] ]]>
[#] ]]>

In a small proof-of-concept study, valproic acid administered to HIV infected adults for three months with enfuvirtide accelerated the clearance of HIV from latent T cells and decreased the frequency of latent cell infection significantly in three of four patients. These findings suggest valproic acid may be useful in decreasing the HIV reservoir and eliminating more of the virus from infected cells. [#] [#]

Valproic acid dissociates to the active valproate ion in the gastrointestinal (GI) tract. Absorption from the GI tract varies with dosage regimens and formulations, but the variances are unlikely to have a clinical effect.

Valproic acid is protein bound in a concentration-dependent manner; the free fraction increases from 10% to nearly 20% at 40 mcg/ml and 130 mcg/ml concentrations, respectively. Cerebrospinal fluid concentrations approximate the unbound plasma concentrations at 10%. Protein binding is saturable; unbound valproic acid pharmacokinetic measurements are linear. Mean terminal half-life ranges from 9 to 16 hours.

Valproic acid is almost entirely hepatically metabolized. Nearly 40% of a dose is glucuronidated, and mitochondrial beta-oxidation accounts for more than 40% of the dose. Other oxidative metabolism accounts for the remaining administered drug. Less than 3% of drug is recovered unchanged. Children between the ages of 3 months and 10 years have 50% higher clearance rates. Elderly clearance rates are reduced by 39% to 44%. [#]

Valproic acid is in FDA Pregnancy Category D. The drug may be teratogenic in humans. Neural tube defects and other congenital anomalies may occur, and clotting abnormalities may develop in pregnant women. [#] ]]>

Hepatic failure resulting in fatalities has occurred in people taking valproic acid, usually within the first 6 months of treatment. Hepatotoxicity may be preceded by symptoms of malaise, weakness, lethargy, facial edema, anorexia, and vomiting. Valproic acid should be discontinued immediately in the presence of suspected or apparent hepatic dysfunction; dysfunction may progress despite drug discontinuation. [#]

Adverse effects commonly associated with divalproex sodium, an oral salt dosage form of valproic acid, include headache; asthenia; nausea, vomiting, abdominal pain, and diarrhea; somnolence; dizziness; and tremor. Photosensitivity, Steven-Johnsons Syndrome, and rare cases of toxic epidermal necrosis have occurred. Minor, dose-related elevations of hepatic enzymes occur frequently. [#] ]]>

Valproic acid may interact with concurrently administered medications capable of hepatic enzyme induction; for example, phenytoin, cyclobenzaprine, and phenobarbital can double valproic acid clearance. Cytochrome P450 (CYP) inhibitors have a smaller effect on valproic acid clearance, because CYP-mediated oxidation of valproic acid is secondary to glucuronidation and beta-oxidation. [#]

Valproic acid is a weak inhibitor of some hepatic enzymes and is able to displace plasma protein-bound drugs. These effects increase the serum levels of cyclobenzaprine, diazepam, phenobarbital, phenytoin, and some other medications.

Concurrent valproic acid and zidovudine administration results in a 38% decrease in zidovudine clearance but half-life is unaffected.

Coadministration of valproic acid and aspirin results in a fourfold increase in the free fraction of valproic acid, compared to monotherapy due to inhibition of beta-oxidation. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>Depakene Extended Release Tablets Prescribing Information from the FDA web site [PDF]. A more current version may be available on the manufacturer's web site.
Cohen J. HIV/AIDS. Report of novel treatment aimed at latent HIV raises the 'c word'. Science. 2005 Aug 12;309(5737):999-1000. No abstract available.
DiCenzo R, Peterson D, Cruttenden K, Morse G, Riggs G, Gelbard H, Schifitto G. Effects of valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2004 Nov;48(11):4328-31.
Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand A, Landay AL, Coombs RW, Richman DD, Mellors JW, Coffin JM, Bosch RJ, Margolis DM. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 2005 Aug 13-19;366(9485):549-55.
Smith SM. Valproic acid and HIV-1 latency: beyond the sound bite. Retrovirology. 2005 Sep 19;2:56.
Use of Valproic Acid to Purge HIV From Resting CD4+ Memory Cells. Available at: Accessed 12/11/07]]>
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Phone: 800-633-9110]]>