Drugs

PSI-5004

Other Names: (+)/(-)-FTC, RCV, Racivir Drug Class: Nucleoside Reverse Transcriptase Inhibitors
Molecular Formula: C8 H10 F N3 O3 S
Registry Number: 143491-54-7 (CAS) Chemical Name: 4-amino-5-fluoro-1-[(2S,5R)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one Chemical Class: Pyrimidine Nucleosides Organization: Pharmasset, Inc. (acquired by Gilead Sciences, Inc. in 2011) Phase of Development: II (discontinued)

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PSI-5004

PSI-5004

Molecular Weight: 247.249

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 Antiviral Chemistry & Chemotherapy journal article,3 Gilead Sciences, Inc. Press Release,4 and HIV i-BASE/Treatment Action Group 2013 Pipeline Report5)

NOTE: The development of PSI-5004 for HIV treatment has been discontinued.


The study of PSI-5004 as an NRTI HIV medicine was discontinued. The last clinical trial activity involving PSI-5004 appears to have been in 2008.5


Pharmacology


Mechanism of Action: NRTI. PSI-5004 (also known as Racivir) is a cytidine analog consisting of a 50:50 racemic mixture of the (–)- and (+)-beta-enantiomers of 2’-deoxy-3’-thia-5-fluorocytosine (FTC).3,6 As a nucleoside analog, PSI-5004 is phosphorylated by host cellular kinases to its active 5′-triphosphate metabolites, which inhibit the activity of HIV-1 reverse transcriptase by competing with natural substrates and causing DNA chain termination following incorporation into viral DNA.7,8 As triphosphates, both the (+) and the (-) enantiomers of FTC have exhibited activity against both HIV and hepatitis B virus (HBV).9

Half-life (T½): In an oral dose-escalation study of once-daily PSI-5004 in combination with stavudine and efavirenz in HIV-infected participants, the plasma half-life of PSI-5004 was approximately 6 hours on Days 1 and 14 for the 200- and 400-mg treatment groups and 3 hours on Days 1 and 14 for the 600-mg treatment group.9

Metabolism/Elimination: Studies have indicated that (+)-FTC is deaminated to the nontoxic metabolite (+)-FTU, while the (-) enantiomer appears stable to deamination.3 In an oral dose-escalation study of PSI-5004 200, 400, and 600 mg in HIV-infected participants, the majority of the total dose (70% to 80%) was excreted into the urine over 24 hours, with approximately 40% to 45% of the drug excreted unchanged as PSI-5004 and 27% to 40% excreted as the (+)-FTU metabolite.9

Resistance: Previous in vitro studies have demonstrated that each enantiomer of PSI-5004 selects for different mutations on the HIV-1 reverse transcriptase gene; the (-) enantiomer selects for M184V, whereas the (+) enantiomer selects for T215Y.9

In a Phase II study (NCT00121979), after 28 days of therapy in treatment-experienced adults, PSI-5004 600 mg demonstrated effective activity in reducing viral load in virological responders harboring the M184V mutation and fewer than 3 thymidine analogue-associated mutations (TAMs).10,11


Clinical Trials


Study Identifiers: Study 101; NCT00040300
Sponsor: Pharmasset
Phase: Ib/IIa
Study Purpose: The purpose of this open-label dose-escalation study was to evaluate the safety, pharmacokinetics, and antiviral activity of PSI-5004 versus lamivudine, each in combination with stavudine and efavirenz.
Study Population: Participants were HIV-infected, treatment-naive adult males who had HIV RNA >5,000 copies/mL and CD4 counts >50 cells/mm3.
Dosing: Three groups of participants were sequentially assigned to each receive 14 days of orally administered PSI-5004 200, 400, and 600 mg once daily, in combination with stavudine and efavirenz. A control group received lamivudine in combination with stavudine and efavirenz over 14 days. On Day 15, all participants stopped their PSI-5004-containing regimens and were allowed to start on other ARV therapy. Approximately one-half of participants were followed up through an additional 21 days.6,9,12
Selected Study Results:


Study Identifiers: Study 201; NCT00121979
Sponsor: Pharmasset
Phase: II
Study Purpose: The purpose of this study was to evaluate the safety and efficacy of PSI-5004 versus lamivudine, each in combination with a background regimen.
Study Population:
  • Participants were HIV-infected, treatment-experienced adults who had the M184V HIV mutation.
  • Participants were receiving a stable ART regimen that contained lamivudine for at least 60 days prior to screening and were failing their current ART regimen.
  • Participants had HIV RNA ≥2,000 copies/mL and CD4 counts ≥50 cells/mm3.

Dosing: Participants were randomly assigned to receive either PSI-5004 600 mg (in place of lamivudine) or continued lamivudine therapy, each in combination with their existing background regimens over 28 days. After 28 days, participants who were receiving PSI-5004 could continue with PSI-5004 treatment (open-label), with or without an optimized background regimen, for up to an additional 20 weeks. Participants were then followed for an additional 4 weeks.6,10,13
Selected Study Results:
  • Pharmasset, Inc. news release, 2008: Racivir - New HIV Drug
  • CROI, 2007: Racivir Demonstrates Safety and Efficacy in Patients Harboring HIV with the M184V Mutation and <3 TAM


Adverse Events


In Study 101 (NCT00040300), the most common adverse events (AEs) were mild to moderate dizziness and headache, both of which were possibly related to the study drug. Other AEs occurring in the trial on more than 3 occasions were impaired concentration, nausea, fatigue, common cold, and ocular discomfort. Heartburn, possibly related to PSI-5004, occurred in 1 participant receiving PSI-5004 600 mg. One participant discontinued the trial because of moderate nausea and vomiting associated with mild dizziness, possibly related to PSI-5004 or efavirenz. There were no relevant electrocardiogram (ECG), biochemical, or hematological changes. One participant who had chronic hepatits B and was receiving PSI-5004 400 mg had elevated AST and ALT levels during the course of the study period and experienced a chronic hepatitis B flare-up upon cessation of therapy.9

In Study 201 (NCT00121979), no severe AEs related to study drug treatment after 28 days of therapy were reported.13


Drug Interactions


PSI-5004 drug interactions are currently unknown.


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/143491-54-7. Last accessed on January 9, 2017.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on January 9, 2017.
  3. Hurwitz SJ, Otto MJ, Schinazi RF. Comparative pharmacokinetics of Racivir, (+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected humans. Antivir Chem Chemother. 2005;16(2):117-27. Available at: http://www.intmedpress.com/serveFile.cfm?sUID=48452b2e-7c1d-49c7-9e79-7d04bd125fc2. Last accessed on January 9, 2017.
  4. Gilead Sciences, Inc.: Press Release, dated November 21, 2011. Gilead Sciences to Acquire Pharmasset, Inc. for $11 Billion. Available at: http://www.gilead.com/news/press-releases/2011/11/gilead-sciences-to-acquire-pharmasset-inc-for-11-billion. Last accessed on January 9, 2017.
  5. Clayden P, Collins S, Daniels C, et al. HIV i-BASE/Treatment Action Group. 2013 Pipeline Report. Benzacar A, ed. June 2013. Available at: http://www.treatmentactiongroup.org/sites/default/files/201306/2013%20Pipeline%20Report.pdf. Last accessed on January 9, 2017.
  6. Pharmasset, Inc.: Press Release, dated September 17, 2008. Racivir – New HIV Drug. Available from National AIDS Treatment Advocacy Project (NATAP) at: http://www.natap.org/2008/HIV/091708_01.htm. Last accessed on January 9, 2017.
  7. Herman BD and Sluis-Cremer N. Molecular Pharmacology of Nucleoside and Nucleotide HIV-1 Reverse Transcriptase Inhibitors. In: Gallelli L, ed. Pharmacology. InTech, DOI: 10.5772/32969; 2012: p. 63-81. Available at: http://www.intechopen.com/books/pharmacology/molecular-pharmacology-of-nucleoside-and-nucleotide-hiv-1-reverse-transcriptase-inhibitors. Last accessed on January 9, 2017.
  8. Wilson JE, Martin JL, Borroto-Esoda K, et al. The 5'-triphosphates of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine equally inhibit human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 1993 Aug;37(8):1720-2. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC188052/. Last accessed on January 9, 2017.
  9. Herzmann C, Arastèh K, Murphy RL, et al. Safety, pharmacokinetics, and efficacy of (+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine with efavirenz and stavudine in antiretroviral-naïve human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2005 Jul;49(7):2828-33. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1168662/. Last accessed on January 9, 2017.
  10. Pharmasset. Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Exploring the Safety, Tolerability, and Antiviral Effect of Substituting 600 mg Racivir for 3TC in HIV-Infected Subjects Who Have the M184V Mutation and Are Currently Failing on a HAART Regimen Containing Lamivudine. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 18, 2005. NLM Identifier: NCT00121979. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00121979. Last accessed on January 9, 2017.
  11. De La Rosa A, Lloyd R Jr, Otto MJ. Clonal analysis of samples from virological responders receiving Racivir in the RCV 201 Study. Abstract presented at: 16th International HIV Drug Resistance Workshop: Basic Principles & Clinical Implications; June 12-16, 2007; Barbados, West Indies. Abstract 24. Available at: http://www.intmedpress.com/serveFile.cfm?sUID=36a5d521-cb5c-4d51-9490-936bf008c2c3. Last accessed on January 9, 2017.
  12. Pharmasset. A 14-Day Study of Racivir When Used in Combination in HIV-Infected Males. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 24, 2002. NLM Identifier: NCT00040300. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00040300. Last accessed on January 9, 2017.
  13. Cahn P, Sosa N, Wiznia A, et al. Racivir Demonstrates Safety and Efficacy in Patients Harboring HIV with the M184V Mutation and <3 TAM. Paper presented at: 14th Conference on Retroviruses and Opportunistic Infections (CROI); February 25-28, 2007; Los Angeles, CA. Paper 488. Available at: http://www.retroconference.org/2007/Abstracts/30151.htm. Last accessed on May 28, 2013.


Last Reviewed: January 9, 2017