Mechanism of Action: Nucleoside reverse transcriptase inhibitor. Censavudine (OBP-601; BMS-986001; 4′-Ed4T), a thymidine analog, is phosphorylated by host cellular kinases to its active triphosphate metabolite (4′-Ed4T triphosphate or 4′-Ed4TTP), with an intracellular half-life of approximately 8.0 to 9.7 hours.4 4′-Ed4TTP inhibits the activity of HIV-1 reverse transcriptase by competing with natural substrates and causing DNA chain termination after incorporating itself into viral DNA.5,6 In vitro, censavudine exhibits more potent activity against HIV-2 than against HIV-1.7,8
Half-life (T½): Apparent half-life ranged from 2.3 to 3.7 hours in a single oral-dose escalation study of censavudine in healthy participants in the fed state (10 to 900 mg) and fasting state (100 and 300 mg).9
Metabolism/Elimination: Approximately 60% to 95% of an oral censavudine dose was excreted unchanged in urine in a single oral-dose escalation study of healthy participants in the fed state (10 to 900 mg) and fasting state (100 and 300 mg).9
Resistance: In vitro experiments have shown that virus containing the K65R, Q151M (without M184), and possibly L74V mutations demonstrate hypersusceptibility to censavudine. Meanwhile, thymidine analogue mutation pattern 1 (TAM1) pathway virus has reduced susceptibility, exhibiting increasing fold changes with increasing numbers of mutations. Decreased susceptibility was also associated with virus containing the T69 insertion complex and with a Q151M virus that also contained M184V. Compared to wild-type (wt) virus, TAM2 pathway virus exhibited a 6- to 8-fold reduced susceptibility to censavudine, regardless of the number of thymidine analogue mutations (TAMs). The M184V single substitution has been selected by censavudine in vitro and was shown to induce a 2.3-fold decrease in susceptibility to censavudine.10,11
Censavudine has demonstrated potent in vitro activity against HIV-2, including HIV-2 mutants containing the K65R and Q151M reverse transcriptase substitutions. The M184V mutation in HIV-2 resulted in a 15-fold resistance to censavudine relative to the wild-type HIV-2 strain.7
In a Phase IIa dose-escalation study (EUDRACT number 2008-004810-29) of 100 to 600 mg of censavudine monotherapy in treatment-experienced adults, no NRTI-associated resistance mutations were selected after 10 days of monotherapy.11-13 Three participants had a decreased response to censavudine on Day 11, but did not have NRTI-associated mutations at baseline or on Day 11. Three other participants who had TAMs responded well to censavudine treatment.13
A Phase IIb study (AI467003) evaluated 100 to 400 mg of censavudine versus tenofovir DF, each administered with efavirenz and lamivudine in treatment-naive adults. Week 48 analysis showed that a higher percentage of participants developed treatment-emergent NNRTI and NRTI mutations in the censavudine groups (regardless of dose) than in the tenofovir DF group.14
Dosing in Clinical Trials
Food does not significantly affect the pharmacokinetics of censavudine.9
: 2008-004810-29 (EUDRACT Number)13
: Dose-escalation study to evaluate the antiviral activity, safety, and pharmacokinetics of censavudine over 10 days.
: HIV-infected, treatment-experienced adults (off antiretroviral [ARV] therapy for at least 3 months)
: Censavudine was administered as monotherapy. Four groups of participants were sequentially assigned to receive either censavudine (100, 200, 300, or 600 mg) or placebo once daily.12,13,15
(See references cited above for information on study results.)
: AI467003; NCT0148904614,16
: Dose-response study to identify a safe and effective dose of censavudine when combined with efavirenz and lamivudine.
: HIV-infected, treatment-naive adults
: Censavudine was administered orally and once daily. Participants were randomized to one of the following four groups:
- Censavudine 100 mg + censavudine matching placebo + efavirenz + lamivudine
- Censavudine 200 mg + censavudine matching placebo + efavirenz + lamivudine
- Censavudine 400 mg + efavirenz + lamivudine
- Tenofovir DF 300 mg + efavirenz + lamivudine.14,16
(See references cited above for information on study results.)
At high exposures, the major preclinical toxicities with censavudine have been hematological. A nonclinical renal and bone toxicity study of censavudine in which censavudine was administered orally for 6 months in rats (50 to 300 mg/kg/day) and monkeys (50 to 200 mg/kg/day) found no evidence of censavudine-related changes in renal function, biomarkers of renal toxicity, serum phosphate, calcium, or biomarkers of bone formation or resorption.17
The in vitro cytotoxicity of censavudine has been compared with four other NRTIs (tenofovir DF, zidovudine, stavudine, and abacavir) in cell cultures of human renal proximal tubule epithelium, muscle, preadipocytes, and differentiated adipocyctes. Based on in vitro cytotoxicity parameters that were measured (total cell protein and ATP content, cell mitochondrial ATP8 DNA content, and lactate concentration in the media), censavudine did not significantly reduce mitochondrial DNA and was not cytotoxic in any of the cell culture systems tested. When compared to the four other NRTIs, censavudine was the least cytotoxic, with zidovudine and stavudine being the most cytotoxic.18
In a 10-day dose-escalation study (EUDRACT number 2008-004810-29) of censavudine monotherapy, 22 out of 24 censavudine-treated participants experienced adverse events (AEs), which were mostly mild and unrelated or unlikely related to the study drug. AEs did not appear to be dose related. There were no study discontinuations due to an AE and Grade 4 AEs. When compared to participants receiving placebo, a greater proportion of participants receiving censavudine reported Grade 2 and 3 AEs. Two censavudine-unrelated serious adverse events (SAEs) occurred in the 600-mg dose group. The most common AEs in the censavudine groups (occurring in more than 10% of participants) were abdominal pain, lymphadenopathy, nausea, headache, and fatigue.13
In the Phase IIb study (AI467003) of censavudine versus tenofovir DF through 48 weeks, two censavudine-related SAEs (atypical drug eruption; thrombocytopenia) and two tenofovir DF-related SAEs (drug induced liver injury; depression and lipodystrophy) led to study discontinuation. One non-study drug-related death occurred. No Grade 2 to 4 AE trends were identified. Grade 2 to 4 laboratory abnormalities were transient and most did not result in study discontinuation.14 In a separate evaluation of bone and metabolic safety data through 48 weeks, bone mineral density (BMD) decline was found to be smaller in the censavudine groups than in the tenofovir DF group. The proportion of participants with greater than 10% or 20% loss of limb fat from baseline was small and was similar between censavudine and tenofovir DF. There was a trend towards accumulation of central and peripheral fat across the censavudine groups, with the highest accumulation in the 400-mg dose group. No meaningful changes in mitochondrial DNA (mtDNA) copy number were seen in any treatment group. A non-dose-related trend for a slight increase in total cholesterol was seen with censavudine treatment but not with tenofovir DF treatment.19
Censavudine drug interactions are currently unknown.
- United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/634907-30-5. Last accessed on November 12, 2015.
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on November 12, 2015.
- Clayden P, Collins S, Frick M, et al. HIV i-BASE/Treatment Action Group. 2015 Pipeline Report. Benzacar A, ed. July 2015. Page 16. Available at: http://www.treatmentactiongroup.org/sites/g/files/g450272/f/201509/2015%20Pipeline%20Report%20Full.pdf. Last accessed on November 12, 2015.
- Wang X, Tanaka H, Baba M, Cheng YC. Retention of Metabolites of 2',3'-Didehydro-3'-Deoxy-4'-Ethynylthymidine, a Novel Anti-Human Immunodeficiency Virus Type 1 Thymidine Analog, in Cells. Antimicrob Agents Chemother. 2009 Aug; 53(8):3317-24. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715651/. Last accessed on November 12, 2015.
- Yang G, Wang J, Cheng Y, et al. Mechanism of Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase by a Stavudine Analogue, 4'-Ethynyl Stavudine Triphosphate. Antimicrob Agents Chemother. 2008 Jun;52(6):2035-42. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2415781/. Last accessed on November 12, 2015.
- Paintsil E, Dutschman GE, Hu R, et al. Intracellular Metabolism and Persistence of the Anti-Human Immunodeficiency Virus Activity of 2',3'-Didehydro-3'-Deoxy-4'-Ethynylthymidine, a Novel Thymidine Analog. Antimicrob Agents Chemother. 2007 Nov;51(11):3870-9. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151449/. Last accessed on November 12, 2015.
- Smith RA, Raugi DN, Wu VH, et al. The nucleoside analog BMS-986001 shows greater in vitro activity against HIV-2 in comparison to HIV-1. Antimicrob Agents Chemother. 2015 Sep 21 [Epub ahead of print]. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26392486. Last accessed on November 12, 2015.
- Smith RA, Raugi DN, Parker K, et al. BMS-986001: A Promising Candidate for HIV-2 Treatment. Abstract presented at: 24th International HIV Drug Resistance Workshop; February 21-22, 2015; Seattle, WA. Abstract 61. Available at: https://www.informedhorizons.com/resistance2015/pdf/RW2015_Book.pdf. Last accessed on November 12, 2015.
- Paintsil E, Matsuda T, Ross J, Schofield J, Cheng YC, Urata Y. A Single-dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of OBP-601, a Novel NRTI, in Healthy Subjects. 16th Conference on Retroviruses and Opportunistic Infections (CROI); February 8-11, 2009; Montreal, Canada. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2009. Available at: http://www.natap.org/2009/CROI/croi_85.htm. Last accessed on November 12, 2015.
- Li Z, Terry B, Olds W, et al. The in vitro cross-resistance profile of the NRTI BMS-986001 against known NRTI resistance mutations. Abstract presented at: International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies; June 5-9, 2012; Sitges, Spain. Abstract 2. Available at: http://www.intmedpress.com/serveFile.cfm?sUID=8ed08ff3-8b0b-4cda-b481-30a670282653. Last accessed on November 12, 2015.
- Li Z, Terry B, Olds W, et al. In Vitro Cross-Resistance Profile of Nucleoside Reverse Transcriptase Inhibitor (NRTI) BMS-986001 against Known NRTI Resistance Mutations. Antimicrob Agents Chemother. 2013 Nov;57(11):5500-8. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811251/. Last accessed on November 12, 2015.
- Hwang C, Zhu L, Chan H, et al. Antiviral activity, exposure-response, and resistance analyses of monotherapy with the novel HIV NRTI BMS-986001 in ART-experienced subjects. Abstract presented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; March 16-18, 2012; Barcelona, Spain. Abstract O_06. Available at: http://regist2.virology-education.com/abstractbook/2012_3.pdf. Last accessed on November 12, 2015.
- Cotte L, Dellamonica P, Raffi F, et al. Randomized Placebo-Controlled Study of the Safety, Tolerability, Antiviral Activity, and Pharmacokinetics of 10-day Monotherapy with BMS-986001, a Novel HIV NRTI, in Treatment-Experienced HIV-1-Infected Subjects. J Acquir Immune Defic Syndr. 2013 Jul 1;63(3):346-54. Available at: http://www.natap.org/2013/HIV/Randomized_Placebo_Controlled_Study_of_the_Safety,.13.pdf. Last accessed on November 12, 2015.
- Gupta SK, Lombaard J, Echevarria J, et al. HIV NRTI BMS-986001 in Antiretroviral-Naïve Subjects: Week 24/48 Analyses. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 5-9, 2014; Washington, DC. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Available at: http://www.natap.org/2014/ICAAC/ICAAC_28.htm. Last accessed on November 12, 2015.
- Cotte L, Dellamonica P, Raffi F, et al. A Phase-Ib/IIa Dose-Escalation Study of OBP-601 (4’-ethynyl-d4T, Festinavir) in Treatment-Experienced, HIV-1-Infected Patients. Abstract presented at: 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2010; Boston, MA. Abstract H-933. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=d89fb4da-4268-4d6b-88ee-4f4ebcd548de&cKey=74572456-29b9-410f-8a57-972c2b0676c3&mKey=%7b93AEED6A-54D4-4EF6-99BD-A9B3CE9FACD9%7d. Last accessed on November 12, 2015.
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- Guha M, Pilcher G, Moehlenkamp J, et al. Absence of renal and bone toxicity in non-clinical studies of BMS-986001, a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus (HIV). Abstract presented at: 19th International AIDS Conference; July 22-27, 2012; Washington DC. Abstract TUPE041. Available at: http://pag.aids2012.org/abstracts.aspx?aid=16832. Last accessed on November 12, 2015.
- Wang F, Flint O. The HIV NRTI BMS-986001 does not degrade mitochondrial DNA in long term primary cultures of cells isolated from human kidney, muscle and subcutaneous fat. Abstract presented at: 19th International AIDS Conference; July 22-27, 2012; Washington DC. Abstract TUPE042. Available at: http://pag.aids2012.org/abstracts.aspx?aid=17957. Last accessed on November 12, 2015.
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Last Reviewed: November 16, 2015