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Investigational

PSI-5004  Audio icon

Other Names: (+)/(-)-FTC, Racivir, RCV
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
Company: Pharmasset, Inc. (acquired by Gilead Sciences, Inc. in 2011)
Phase of Development: Phase II
Chemical Image:
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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 and Gilead Sciences, Inc. Press Release4)
Patent Version Content

Pharmacology


Mechanism of Action: Nucleoside reverse transcriptase inhibitor. 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).3,5 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.6,7 As triphosphates, both the (+) and the (-) enantiomers of FTC have exhibited activity against both HIV and hepatitis B virus (HBV).8

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.8

Metabolism/Elimination: Studies have indicated that (+)-FTC is deaminated to the non-toxic 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.8

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.8

In a Phase II study, after 28 days of treatment 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 three thymidine analogue associated mutations (TAMs).9,10


Dosing in Clinical Trials


Study Identifiers: Study 1015; NCT0004030011
Phase: Ib/IIa
Study Purpose: Dose-escalation study to evaluate the safety, pharmacokinetics, and antiviral activity of PSI-5004 versus lamivudine, each in combination with stavudine and efavirenz
Study Population: HIV-infected, treatment-naive adult males
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.5,8,11,12
(See references cited above for information on study results.)

Study Identifiers: Study 2015; NCT001219799
Phase: II
Study Purpose: Study to evaluate the safety and efficacy of PSI-5004 versus lamivudine, each in combination with a background regimen
Study Population: HIV-infected, treatment-experienced adults who have the M184V HIV mutation and are receiving lamivudine as a component of their current failing antiretroviral therapy (ART) regimen
Dosing: PSI-5004 600 mg (in place of lamivudine) versus continued lamivudine therapy, each in combination with a background regimen over 28 days.5,9,13
(See references cited above for information on study results.)


Adverse Events


In Study 101, the most common adverse events were mild to moderate dizziness and headache (both events possibly related to the study drug). Other adverse events occurring in the trial on more than three 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 levels of the liver enzymes aspartate aminotransferase and alanine aminotransferase during the course of the study period and experienced a chronic hepatitis B flare-up upon cessation of therapy.8

In Study 201, no severe adverse events 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 October 25, 2014.
  2. 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 October 25, 2014.
  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 October 25, 2014.
  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 October 25, 2014.
  5. 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 October 25, 2014.
  6. 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 October 25, 2014.
  7. 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 October 25, 2014.
  8. 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 October 25, 2014.
  9. 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 October 25, 2014.
  10. 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 October 25, 2014.
  11. 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 October 25, 2014.
  12. Otto MJ, Arastèh K, Kreckel P, et al. Sustained Anti-HIV-1 Effect of Racivir Combined with D4T and Sustiva Following a 14-day Treatment of Infected Volunteers. Paper presented at: 10th Conference on Retroviruses and Opportunistic Infections (CROI); February 10-14, 2003; Boston, MA. Paper 552. Available at: http://www.retroconference.org/2003/cd/Abstract/552.htm. Last accessed on May 28, 2013.
  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: October 25, 2014

Last Updated: October 25, 2014


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