Drug Description

Maraviroc, also known as Selzentry, is a chemokine receptor antagonist that acts as an entry inhibitor. It is designed to prevent HIV infection of CD4 cells by blocking chemokine receptor 5 (CCR5), a coreceptor necessary for HIV entry, from binding to HIV. [1]

References

[1] Intl HIV Drug Resistance Wkshp 13th, 2004. Abstract 6.

HIV/AIDS-Related Uses

Maraviroc, a first-in-its-class, selective, CCR5-coreceptor antagonist, was granted accelerated regulatory review in the United States and Europe in February 2007. [1] In April 2007, the FDA's Antiviral Drugs Evaluation Committee unanimously recommended accelerated approval of maraviroc for treatment-experienced patients. [2] Maraviroc received accelerated approval by the FDA on August 6, 2007. The accelerated approval was based on 24-week, interim data from two ongoing trials. [3] [4] After evaluation of longer-term safety and efficacy data, the FDA granted full approval of maraviroc on November 25, 2008. [5] On November 20, 2009, the FDA approved a supplemental new drug application (NDA) to expand the indication for maraviroc to include combination antiretroviral treatment of therapy-naïve adults infected with CCR5-tropic HIV-1 virus. [6]

The expanded indication of maraviroc to treatment-naïve adults is based upon data collected through 96 weeks from Study A4001026, demonstrating safety and efficacy. In this Phase 2b/3 study of treatment-naïve subjects, the incidence of AIDS-defining Category C events when adjusted for exposure was lower for maraviroc compared to efavirenz (1.8 compared to 2.4 events per 100 patient-years of exposure). [7]

Maraviroc is approved for use in combination with other antiretroviral (ARV) medications for the treatment of adults infected with only CCR5-tropic HIV-1 (R5 virus). In treatment-naïve subjects, more subjects treated with maraviroc experienced virologic failure and developed lamivudine resistance compared to efavirenz. The safety and efficacy of maraviroc have not been established in pediatric patients. Maraviroc is not approved for use in patients 16 years of age or younger. [8] [9] [10] Safety and efficacy are not established in treatment-naive HIV infected people or in those with dual- or mixed-tropic or with CXCR4-tropic virus. [11] Tropism testing with a highly sensitive tropism assay is required for the appropriate use of maraviroc. [12]

References

[1] Pfizer Maraviroc EAP - Interested Health Care Professional. Available at: http://www.maraviroceap.com/interested_healthcare_professional/overview.aspx. Accessed 08/27/08.

[2] FDA Pfizer Inc, Maraviroc Tablets NDA 22-128, Antiviral Drugs Advisory Commitee (AVDAC) Briefing Document, April 24, 2007. Available at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4283b1-01-Pfizer.pdf. Accessed 08/27/08.

[3] Pfizer Pfizer's Selzentry (Maraviroc) Tablets, Novel Treatment for HIV, Approved by FDA [press release], August 6, 2007. Available at: http://mediaroom.pfizer.com/portal/site/pfizer/index.jsp?ndmViewId=news_view&newsId=20070806005899&newsLang=en. Accessed 08/27/08.

[4] FDA News: FDA Approves Novel Antiretroviral Drug [press release], August 6, 2007. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01677.html. Accessed 08/27/08.

[5] Pfizer News and Media: Press Releases. Pfizer¿s Novel HIV/AIDS Treatment Selzentry Becomes the Latest Fully Approved Antiretrovial for Treatment-Experienced HIV Patients [press release], November 25, 2008. Available at: http://www.pfizer.com/news/press_releases/pfizer_press_releases.jsp. Accessed 11/26/08.

[6] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

[7] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

[8] Pfizer Pfizer's Selzentry (Maraviroc) Tablets, Novel Treatment for HIV, Approved by FDA [press release], August 6, 2007. Available at: http://mediaroom.pfizer.com/portal/site/pfizer/index.jsp?ndmViewId=news_view&newsId=20070806005899&newsLang=en. Accessed 08/27/08.

[9] FDA News: FDA Approves Novel Antiretroviral Drug [press release], August 6, 2007. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01677.html. Accessed 08/27/08.

[10] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

[11] FDA List Serve Archive, August 6, 2007. Available at: http://www.fda.gov/oashi/aids/listserve/listserve2007.html#080607. Accessed 08/27/08.

[12] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

Dosing Information

Oral. [1]

Dosage Form

Maraviroc is available as 150- and 300-mg blue, oval film-coated tablets. The recommended dose of maraviroc differs based on concomitant medications because of drug interactions. Maraviroc can be taken with or without food. Maraviroc must be given in combination with other antiretrovial medications. Dose adjustments with concomitant medications are as follows:

- When given with potent CYP3A inhibitors (with or without a CYP3A inducer)--including protease inhibitors (except tipranavir/ritonavir); delavirdine; ketoconazole, itraconazole, clarithromycin; and other potent CYP3A inhibitors (e.g., nefazodone, telithromycin)--the recommended dose is maraviroc 150 mg twice daily.
- When given with NRTIs, tipranavir/ritonavir, nevirapine, raltegravir, and other drugs that are not potent CYP3A inhibitors or CYP3A inducers, the recommended dose is maraviroc 300 mg twice daily.
- When given with potent CYP3A inducers (without a potent CYP3A inhibitor)--including efavirenz; rifampin; etravirine; and carbamazepine, phenobarbital, and phenytoin--the recommended dose is maraviroc 600 mg twice daily. [2]

Safety and efficacy have not been established in pediatric patients; therefore, maraviroc should not be used in patients younger than 16 years of age. [3]

For patients with impaired renal function (CrCl ≤ 80 mL/min), recommended doses of maraviroc are based on the results of a pharmacokinetic study conducted in healthy subjects with various degrees of renal impairment. The pharmacokinetics of maraviroc in subjects with mild and moderate renal impairment was similar to that in subjects with normal renal function. No dose adjustment is recommended for patients with mild or moderate renal impairment receiving maraviroc with or without a potent CYP3A inhibitor or inducer. [4]

If patients with severe renal impairment or end-stage renal disease (ESRD) not receiving a concomitant potent CYP3A inhibitor or inducer experience any symptoms of postural hypotension while taking maraviroc 300 mg twice daily, the dose should be reduced to 150 mg twice daily. No studies have been performed in subjects with severe renal impairment or ESRD co-treated with potent CYP3A inhibitors or inducers. Hence, no dose of maraviroc can be recommended, and it is contraindicated for these patients. [5]

Storage

Film-coated tablets should be stored at 25 C (77 F), with excursions permitted between 15 C and 30 C (59 F and 86 F). Maraviroc tablet shelf-life is 24 months. [6]

References

[1] Interscience Conf on Antimicrobial Agents and Chemotherapy 43rd, 2003. Abstract H-874.

[2] FDA Selzentry Prescribing Information, 11/20/09. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022128s002lbl.pdf. Accessed on: 6/3/10.

[3] FDA Selzentry Prescribing Information, 11/20/09. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022128s002lbl.pdf. Accessed on: 6/3/10.

[4] FDA Selzentry (maraviroc) labeling changes for patients with renal impairment [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm214196.htm. Accessed on: 6/3/10.

[5] FDA Selzentry (maraviroc) labeling changes for patients with renal impairment [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm214196.htm. Accessed on: 6/3/10.

[6] FDA Selzentry Prescribing Information, 08/02/07, p. 18. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

Pharmacology

Maraviroc binds to CCR5, preventing HIV from binding to this receptor. When CCR5 is unavailable, CCR5-tropic HIV cannot engage a CD4 cell to infect the cell. The CCR5-tropic variant of the virus is common in earlier HIV infection, whereas viruses adapted to use the CXCR4 receptor gradually become dominant as HIV infection progresses. [1] Maraviroc did not display efficacy against CXCR4-tropic or mixed- or dual-tropic virus in Phase II efficacy studies. [2]

Peak plasma concentrations (Cmax) of maraviroc are achieved between 0.5 and 4 hours after single oral doses of maraviroc 1,200 mg in healthy volunteers. Maraviroc pharmacokinetics are not dose proportional. The absolute bioavailability of a 100-mg dose is 23% and is predicted to be 33% after a 300-mg dose. [3]

Maraviroc is metabolized by the cytochrome P450 (CYP) liver enzyme system, primarily by CPY3A; metabolites of maraviroc are inactive against HIV-1. The terminal half-life of maraviroc at steady-state is between 14 and 18 hours. Maraviroc, rather than metabolites, was the main component recovered. [4]

Maraviroc is moderately protein bound (approximately 76%) and has a volume of distribution of approximately 194 liters. Renal clearance accounts for approximately 25% of total clearance of maraviroc. [5] A study compared the pharmacokinetics of a single 300 mg dose of maraviroc in subjects with severe renal impairment and end-stage renal disease (ESRD) to healthy volunteers.  Geometric mean ratios for maraviroc Cmax and AUCinf were 2.4-fold and 3.2-fold higher respectively for subjects with severe renal impairment, and 1.7-fold and 2.0-fold higher respectively for subjects with ESRD as compared to subjects with normal renal function in this study. Hemodialysis had a minimal effect on maraviroc clearance and exposure in subjects with ESRD. Exposures observed in subjects with severe renal impairment and ESRD were within the range observed in previous maraviroc 300 mg single-dose studies in healthy volunteers with normal renal function. However, maraviroc exposures in the subjects with normal renal function in this study were 50% lower than that observed in previous studies. Based on the results of this study, no dose adjustment is recommended for patients with renal impairment receiving maraviroc without a potent CYP3A inhibitor or inducer. However, if patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking maraviroc 300 mg twice daily, their dose should be reduced to 150 mg twice daily. [6] 

In addition, the study compared the pharmacokinetics of multiple dose maraviroc in combination with saquinavir/ritonavir 1000/100 mg twice daily (a potent CYP3A inhibitor combination) for 7 days in subjects with mild renal impairment and moderate renal impairment to healthy volunteers with normal renal function. Subjects received 150 mg of maraviroc at different dose frequencies (healthy volunteers – every 12 hours; mild renal impairment – every 24 hours; moderate renal impairment – every 48 hours). Compared to healthy volunteers (dosed every 12 hours), geometric mean ratios for maraviroc AUCtau, Cmax, and Cmin were 50% higher, 20% higher, and 43% lower, respectively for subjects with mild renal impairment (dosed every 24 hours). Geometric mean ratios for maraviroc AUCtau, Cmax, and Cmin were 16% higher, 29% lower, and 85% lower, respectively for subjects with moderate renal impairment (dosed every 48 hours) compared to healthy volunteers (dosed every 12 hours). Based on the data from this study, no adjustment in dose is recommended for patients with mild or moderate renal impairment. [7]

Maraviroc is in Pregnancy Category B. No adequate and well-controlled studies have been conducted in pregnant women. However, the incidence of fetal malformations in animal studies, conducted at doses up to 20-fold higher than recommended human doses, was not increased. To monitor maternal-fetal outcomes of pregnant women exposed to maraviroc and other ARV medications, an Antiretroviral Pregnancy Registry has been established. Physicians may register patients online at http://www.APRegistry.com or by calling 800-258-4263. [8]

In a small, Phase I study conducted in 2003, 24 HIV infected adults with CCR5-tropic HIV were randomized to receive maraviroc 25 mg once daily, 100 mg twice daily, or placebo. Steady-state drug levels were reached within 7 days, with more favorable drug levels achieved in the fasted state. By Day 14, those receiving 100 mg doses had experienced a viral load decline of more than 20-fold compared with a nearly threefold reduction in the 25-mg group. The drug was well tolerated, and viral load did not rebound immediately upon cessation of the drug, indicating that a proportion of the receptors remain blocked for some time. [9]

Interim Week 24 results of the two Phase IIb/III placebo-controlled studies MOTIVATE-1 and -2 indicate that treatment with maraviroc plus optimized background therapy (OBT) leads to superior viral control compared with OBT alone. These studies are following a total of 1,049 participants, residing in Europe, Australia, Canada, and the United States, who are triple class resistant, had baseline viral loads of more than 5,000 copies/ml, and had baseline CD4 counts of approximately 150 cells/mm3. With maraviroc treatment, these participants had viral load reductions of as much as 99% from baseline at a dosage of maraviroc 300 mg once or twice daily while on OBT. CD4 counts in these participants also increased by 56% to 74% from baseline during this time period. [10] Long-term Week 48 data demonstrate that maraviroc plus OBT significantly increase CD4 count compared with OBT alone. In addition, 3 times as many participants receiving maraviroc plus OBT achieved undetectable viral load levels compared with those receiving OBT alone. [11]

Because the impairment of CCR5 could have a negative impact on regular immune function, safety studies have been performed in both healthy and HIV-1 infected people at doses of up to 1,200 mg of maraviroc daily for 10 to 28 days. These studies showed that maraviroc did not have an effect on immune function, and no increased frequency or severity in infections was seen. However, an increase in CD4 count also was not seen over this time period. [12]

In an evaluation of 973 treatment-experienced patients in two ongoing Phase III trials, important predictors of virologic success (viral load less than 400 copies/ml at 24 weeks) included the mean predicted trough concentration of maraviroc, the baseline viral load, and the baseline CD4 count. [13]

In the Phase III MERIT study, maraviroc 300 mg twice daily was compared with efavirenz 600 mg once daily, both in combination with zidovudine/lamivudine. A total of 721 treatment-naïve, HIV-infected patients with CCR5-tropic virus and without evidence of HIV resistance were selected to participate. Rates of virologic suppression to less than 400 copies/mL and less than 50 copies/mL were greater in the efavirenz-treated arm and did not reach criteria for noninferiority of maraviroc. [14] [15]

However, a 2008 reanalysis of the MERIT data that used a newer, more sensitive tropism assay identified 104 of the original 721 patients who actually harbored CXCR4-tropic virus. After their exclusion, analysis of only patients with CCR5-tropic virus resulted in Week 48 virologic suppression rates of 68.5% and 68.3% for maraviroc- and efavirenz-treated arms, respectively, which met criteria for maraviroc noninferiority. [16]

HIV-1 variants with reduced susceptibility to maraviroc have been selected in cell cultures. In an in vitro study using six primary CCR5 HIV-1 isolates, those able to replicate in the presence of high maraviroc concentrations emerged gradually after multiple passages of all isolates. Two isolates resistant to maraviroc continued to use the CCR5 receptor and one isolate developed the ability to use the CXCR4 receptor. In the viruses that remained R5 tropic, two different sets of mutations developed in the gp120 V3 loop region; this and other data suggest that changes in viral tropism are independent of maraviroc. [17] [18] All CCR5 antagonists bind to CCR5 in a pocket formed by transmembrane helices and extracellular loop 2 (ECL2); it appears that subtle differences in occupation of the binding pocket may block replication of some HIV strains. As a result, scientists are optimistic that resistance to an HIV coreceptor antagonist will not necessarily lead to drug class resistance. [19]

Clinical resistance to maraviroc has not yet been fully defined. Virologic failure has been associated with viral tropism switches that occur over time. In an examination of 5 participants who had CCR5-tropic virus at the time of treatment failure while on maraviroc, all 5 had mutations at position 13 or 26 of the V3 loop of CCR5. In an examination of 20 participants who had CXCR4-tropic virus at the time of treatment failure while on maraviroc, 14 participants experienced outgrowth of CXCR4-tropic virus that was undetectable at study entry, whereas 6 experienced a tropism switch. [20] Of the 1,043 patients with R5 virus at screening for the 2 ongoing Phase III trials, 7.6% displayed dual- or mixed-tropism at baseline measurements taken approximately 5 weeks later. In subsequent interim analysis, CXCR4-tropic virus was identified in approximately 60% of patients who failed treatment on maraviroc compared with 6% of patients who experienced treatment failure while on placebo. [21]

References

[1] Intl HIV Drug Resistance Wkshp 13th, 2004. Abstract 6.

[2] FDA List Serve Archive, August 6, 2007. Available at: http://www.fda.gov/oashi/aids/listserve/listserve2007.html#080607. Accessed 08/27/08.

[3] FDA Maraviroc Prescribing Information, 08/02/07, p. 11. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

[4] FDA Maraviroc Prescribing Information, 08/02/07, p. 11. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

[5] FDA Maraviroc Prescribing Information, 08/02/07, pp. 7-8, 11. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

[6] FDA Selzentry (maraviroc) labeling changes for patients with renal impairment [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm214196.htm. Accessed on: 6/3/10.

[7] FDA Selzentry (maraviroc) labeling changes for patients with renal impairment [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm214196.htm. Accessed on: 6/3/10.

[8] FDA Maraviroc Prescribing Information, 08/02/07, pp. 7-8. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

[9] Interscience Conf on Antimicrobial Agents and Chemotherapy 43rd, 2003. Abstract H-443.

[10] Conf Retroviruses Opportunistic Infect 14th, 2007. Abstracts 104aLB and 104bLB.

[11] Pfizer Press Releases: Long-Term Data Reinforce Safety and Efficacy Profile of Pfizer's New HIV Drug Selzentry (Maraviroc) [press release], September 18, 2007. Available at: http://mediaroom.pfizer.com/portal/site/pfizer/index.jsp?ndmViewId=news_view&newsId=20070918006086&newsLang=en. Accessed 08/27/08.

[12] Conf Retroviruses Opportunistic Infect 14th, 2007. Abstract 509.

[13] FDA Maraviroc Prescribing Information, 08/02/07, p. 10. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

[14] AIDS Clin Care Volume 5; September 10, 2007.

[15] FierceBiotech Press Release: Pfizer's Novel HIV/AIDS Treatment Selzentry (Maraviroc) Demonstrates Increased Efficacy Rate In Treatment-Naïve HIV Patients: Results from MERIT ES Data Reanalysis Using Enhanced Sensitivity Tropism Test at 48 Weeks [press release], October 27, 2008. Available at: http://www.fiercebiotech.com/press-releases/pfizers-novel-hiv-aids-treatment-selzentry-maraviroc-demonstrates-increased-efficacy-. Accessed 11/23/08.

[16] Interscience Conf on Antimicrobial Agents and Chemotherapy 48th, 2008. Abstract H-1232a.

[17] Intl HIV Drug Resistance Wkshp 13th, 2004. Abstract 6.

[18] J Gen Virol. 2000;81:2899-904

[19] Conf Retroviruses Opportunistic Infect 12th, 2005. Abstract 96.

[20] FDA Pfizer Inc, Maraviroc Tablets NDA 22-128, Antiviral Drugs Advisory Commitee (AVDAC) Briefing Document, April 24, 2007. Available at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4283b1-01-Pfizer.pdf. Accessed 08/27/08.

[21] FDA Maraviroc Prescribing Information, 08/02/07, pp. 15-6. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

Adverse Events/Toxicity

Hepatotoxicity has been reported with maraviroc use, including a case of possible maraviroc-induced hepatoxicity with allergic features in a study of healthy volunteers. Evidence of a systemic allergic reaction (e.g., pruritic rash, eosinophilia or elevated IgE) prior to the development of hepatotoxicity may occur. Any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms, should be evaluated immediately and consider discontinuing maraviroc. [1]

The safety and efficacy of maraviroc have not been specifically studied in patients with significant underlying liver disorders. Prescribers should use caution when administering maraviroc to patients with preexisting liver dysfunction or who are co-infected with viral hepatitis B or C. [2]

In the two Phase II/III MOTIVATE-1 and -2 studies, adverse effects at Week 24 interim analysis were similar to those that occurred with optimized background therapy (OBT) alone. In these studies, 5% or fewer study participants in both placebo and treatment groups discontinued treatment because of adverse events. [3]

These two studies showed no increase in mortality or malignancy and no clear evidence of hepatotoxicity. However, an increase in Candida, herpes, and influenza infections were observed in these studies. [4]

In 24-week analysis of these two clinical studies, the most common maraviroc-related adverse effects (occurring in more than 8% of patients and more often than in the placebo group) were cough, fever, upper respiratory infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness. Additional adverse effects noted with greater incidence in the once-daily treatment arm included diarrhea, edema, sleep disorders, rhinitis, and urinary abnormalities. Serious adverse events occurred in less than 2% of maraviroc-treated patients and included cardiovascular abnormalities (e.g., angina, heart failure, myocardial infarction), hepatic cirrhosis or failure, cholestatic jaundice, viral meningitis, pneumonia, myositis, osteonecrosis, and rhabdomyolysis. Grade 3 to 4 treatment-emergent laboratory abnormalities occurring in at least 2% of patients included increased bilirubin, amylase, lipase, AST, and ALT levels. [5] At Week 48 analysis of the same studies, the most commonly observed adverse events in the maraviroc plus OBT arm were diarrhea, nausea, fatigue, and headache, all of which occurred with similar incidence in the OBT-only arm. [6]

One case of possible drug-associated hepatotoxicity with allergy has been reported in a study of healthy volunteers. Systemic allergic reaction prior to the onset of hepatotoxicity may involve pruritic rash, eosinophilia, or increased IgE levels. Although no statistically significant increases in Grade 3 to 4 liver function tests have been reported, an increased rate of hepatic adverse events has been observed in treatment-experienced patients. Immediate evaluation and possible discontinuation of maraviroc are warranted in patients exhibiting signs or symptoms of hepatotoxicity, including systemic rash reactions or abnormal liver function tests. [7] To date, only 6% of patients in clinical studies have been coinfected with hepatitis B or C virus; large-scale clinical trials with coinfected individuals are needed to determine the risk of hepatic adverse events in these patients. Maraviroc should be prescribed to patients with HIV and hepatitis coinfections with caution. [8] [9]

Immune reconstitution syndrome has also been reported. In addition, patients taking maraviroc should be monitored for risk of infection because of CCR5-antagonism effects on some immune cells. [10]

Cardiovascular events, including myocardial ischemia or infarction, have been observed at higher rates in maraviroc-treated patients than in placebo. During Phase 3 studies of treatment-experienced individuals, eleven participants (1.3%) who received maraviroc had cardiovascular events including myocardial ischemia and/or infarction (in a total exposure of 609 patient-years, 300 on once daily and 309 on twice daily maraviroc), while no participants who received placebo had such events (total exposure 111 patient-years). The participants who experienced cardiovascular events generally had cardiac disease or cardiac risk factors prior to maraviroc use, and the relative contribution of maraviroc to these events is not known. [11]

In a Phase 2b/3 study of treatment-naïve adults, 3 subjects (0.8%) who received maraviroc had events related to ischemic heart diseases and 5 subjects (1.4%) who received efavirenz had such events (total exposure 506 and 508 patient-years for maraviroc and efavirenz, respectively). [12]

An increase in Candida, herpes, and influenza infections were observed in these studies. [13]

Patients with impaired renal function may have cardiovascular co-morbidities and could be at increased risk of cardiovascular adverse events triggered by postural hypotension. An increased risk of postural hypotension may occur in patients with severe renal insufficiency or in those with end-stage renal disease (ESRD) due to increased maraviroc exposure. Maraviroc should be used in patients with severe renal impairment or ESRD only if they are not receiving a concomitant potent CYP3A inhibitor or inducer. However, the use of maraviroc in these patients should only be considered when no alternative treatment options are available. If patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking 300 mg twice daily, the dose should be reduced to 150 mg twice daily. [14]

Immune reconstitution syndrome has also been reported. Maraviroc antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. During Phase 3 treatment-experienced studies of maraviroc, the overall incidence and severity of infection, as well as AIDS-defining category C infections, was comparable in the treatment groups. In maraviroc treatment arms, there were higher rates of certain upper respiratory tract infections and a higher incidence of Herpes virus infections, but a lower rate of pneumonia, compared to placebo. Patients should be monitored closely for evidence of infections while receiving maraviroc. [15]

While no increase in malignancy has been observed with maraviroc, due to this drug's mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy. [16]

QT prolongation has been observed in animal studies at up to 12 times the recommended human dosage, but no prolongation has been noted in treatment-experienced patients taking recommended dosages. When maraviroc was administered to healthy volunteers at doses higher than the recommended dose, symptomatic postural hypotension was seen at a greater frequency than in placebo. However, when maraviroc was given at the recommended dose to HIV-infected participants in Phase 3 studies, postural hypotension was seen at a rate similar to placebo (approximately 0.5%). [17] The dose-limiting adverse effect in clinical studies, observed at daily doses of maraviroc 600 mg, is postural hypotension. [18] Caution should be used when administering maraviroc in patients with a history of postural hypotension or on concomitant medication known to lower blood pressure. [19]

References

[1] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

[2] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

[3] Conf Retroviruses Opportunistic Infect 14th, 2007. Abstracts 104aLB and 104bLB.

[4] FDA Pfizer Inc, Maraviroc Tablets NDA 22-128, Antiviral Drugs Advisory Commitee (AVDAC) Briefing Document, April 24, 2007. Available at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4283b1-01-Pfizer.pdf. Accessed 08/27/08.

[5] FDA Selzentry Prescribing Information, 08/02/07, pp. 1,4-5. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

[6] Pfizer Press Releases: Long-Term Data Reinforce Safety and Efficacy Profile of Pfizer's New HIV Drug Selzentry (Maraviroc) [press release], September 18, 2007. Available at: http://mediaroom.pfizer.com/portal/site/pfizer/index.jsp?ndmViewId=news_view&newsId=20070918006086&newsLang=en. Accessed 08/27/08.

[7] FDA Selzentry Prescribing Information, 08/02/07, pp. 2-3. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf Accessed 08/27/08.

[8] FDA Selzentry Prescribing Information, 08/02/07, p. 3. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

[9] FDA Selzentry Prescribing Information, 08/02/07, pp. 2-3. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf Accessed 08/27/08.

[10] FDA Selzentry Prescribing Information, 08/02/07, p. 4. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

[11] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

[12] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

[13] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

[14] FDA Selzentry (maraviroc) labeling changes for patients with renal impairment [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm214196.htm. Accessed on: 6/3/10.

[15] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

[16] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

[17] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

[18] FDA Selzentry Prescribing Information, 08/02/07, pp. 6,9. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

[19] FDA Expanded indication for Selzentry (maraviroc) [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm191962.htm. Accessed on: 12/03/09.

Drug and Food Interactions

Coadministration of a 300-mg tablet and a high-fat meal has resulted in reduced Cmax and AUC by 33% each in healthy volunteers. However, because no food restrictions were enacted during clinical trials, maraviroc may be taken with or without food. [1]

Maraviroc is a cytochrome P450 (CYP) 3A and p-glycoprotein (Pgp) substrate and may require dosage adjustments when administered with CYP- or Pgp-modulating medications. CYP3A/Pgp inhibitors such as ketoconazole, lopinavir/ritonavir, ritonavir, saquinavir, and atazanavir increase maraviroc Cmax and AUC; CYP3A/Pgp inducers such as carbamazepine, phenytoin, phenobarbital, rifampin, and efavirenz decrease maraviroc Cmax and AUC. Tipranavir/ritonavir, a CPY3A inhibitor but a Pgp inducer, does not affect maraviroc pharmacokinetics. [2]

References

[1] FDA Selzentry Prescribing Information, 08/02/07, p. 11. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

[2] FDA Selzentry Prescribing Information, 08/02/07, p. 11-3. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

Contraindications

Maraviroc should not be used in patients with severe renal impairment or end-stage renal disease (ESRD) who are taking potent CYP3A inhibitors or inducers. [1]

References

[1] FDA Selzentry (maraviroc) labeling changes for patients with renal impairment [press release]. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm214196.htm. Accessed on: 6/3/10.

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use Maraviroc.

Chemistry

CAS Name

Cyclohexanecarboxamide, 4,4-difluoro-N-((1S)-3-((3-exo)-3- (3-methyl-5-(1-methylethyl)-4H -1,2,4-triazol-4-yl)-8-azabicyclo(3.2.1) oct-8-yl)-1-phenylpropyl)- [1]

CAS Number

376348-65-1 [2]

Molecular Formula

C29-H41-F2-N5-O

Elemental Composition

C67.81%, H8.04%, F7.40%, N13.63%, 03.11%

Molecular Weight

513.67

Physical Description

White to pale-colored powder. [3]

Solubility

Highly soluble across the pH range of 1 to 7.5. [4]

References

[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 08/27/08.

[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 08/27/08.

[3] FDA Selzentry Prescribing Information, 08/02/07, p. 10. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

[4] FDA Selzentry Prescribing Information, 08/02/07, p. 10. Available at: http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf. Accessed 08/27/08.

Further Reading