Mechanism of Action
: Nucleoside reverse transcriptase inhibitor. PSI-5004, a cytidine analog, is a 50:50 racemic mixture of the (–)- and (+)-beta-enantiomers of 2’-deoxy-3’-thia-5-fluorocytosine (FTC).3,4,
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.5,6
As triphosphates, both the (+) and the (-) enantiomers of FTC have exhibited activity against both HIV and hepatitis B virus (HBV).7
: Approximately 6 hours on Days 1 and 14 (200- and 400-mg treatment groups) and 3 hours on Days 1 and 14 (600-mg treatment group) (oral dose-escalation study of once-daily PSI-5004 in combination with stavudine and efavirenz in HIV-infected participants).7
: 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.7
: 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.7
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).8,9
Dosing in Clinical Trials
Phase Ib/IIa (treatment-naive):
- PSI-5004 200, 400, or 600 mg once daily, orally, in combination with stavudine and efavirenz.10
Phase II (treatment-experienced, with M184V mutation and failing current lamivudine-containing regimen):
- PSI-5004 600 mg (in place of lamivudine) compared with continued lamivudine therapy, both in combination with a background regimen.8,11
In a 14-day dose-escalation study of PSI-5004 200, 400, or 600 mg in combination with stavudine and efavirenz in HIV-1-infected, treatment-naive participants, 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 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.7
A Phase II study that compared PSI-5004 600 mg (in place of lamivudine) to continued lamivudine therapy, both in combination with a background regimen, in 42 treatment-experienced adults having HIV-1 with the M184V mutation found no severe adverse events related to study drug treatment after 28 days of therapy.11
PSI-5004 drug interactions are currently unknown.
1. United States National Library of Medicine. ChemIDplus Advanced
2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development
. 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
. Pharmasset, Inc. Racivir – New HIV Drug
. Available at National AIDS Treatment Advocacy Project (NATAP): HIV Articles; September 17, 2008. Accessed May 27, 2013.
. 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.
. 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.
. 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.
. 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. Last accessed May 27, 2013.
. 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.
. 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.
. 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.
Last Reviewed: May 28, 2013
Last Updated: May 28, 2013