Lack of Pharmacokinetic Interaction between Amdoxovir and Reduced- and Standard-Dose Zidovudine in HIV-1-Infected Individuals

• Type of Material: Article
• Authors: Selwyn Hurwitz, Emory University; Ghazia Asif, Emory University; Emilie Fromentin, Emory University; Phillip M. Tharnish, Veterans Affairs Medical Center; Raymond F Schinazi, Emory University
• Language: English
• Date: 2010-03
• Publisher: American Society for Microbiology (ASM)
• Publication Version: Final Published Version
• Copyright Statement: © 2010, American Society for Microbiology
• Final Published Version (URL): http://aac.asm.org/content/54/3/1248
• Title of Journal or Parent Work: Antimicrobial Agents and Chemotherapy
• Volume: 54
• Issue: 3
• Start Page: 1248
• End Page: 1255
• Grant/Funding Information: This work was supported in part by the Emory Center for AIDS Research (CFAR), by NIH grants 5P30-AI-1241980 and 5R37-AI-041980, and by the Department of Veterans Affairs.
• Research Categories: Biology, Microbiology; Chemistry, Biochemistry

Abstract

Amdoxovir (AMDX) inhibits HIV-1 containing the M184V/I mutation and is rapidly absorbed and deaminated to its active metabolite, β-d-dioxolane guanosine (DXG). DXG is synergistic with zidovudine (ZDV) in HIV-1-infected primary human lymphocytes. A recent in silico pharmacokinetic (PK)/enzyme kinetic study suggested that ZDV at 200 mg twice a day (b.i.d.) may reduce toxicity without compromising efficacy relative to the standard 300-mg b.i.d. dose. Therefore, an intense PK clinical study was conducted using AMDX/placebo, with or without ZDV, in 24 subjects randomized to receive oral AMDX at 500 mg b.i.d., AMDX at 500 mg plus ZDV at 200 or 300 mg b.i.d., or ZDV at 200 or 300 mg b.i.d. for 10 days. Full plasma PK profiles were collected on days 1 and 10, and complete urine sampling was performed on day 9. Plasma and urine concentrations of AMDX, DXG, ZDV, and ZDV-5′-O-glucuronide (GZDV) were measured using a validated liquid chromatography-tandem mass spectrometry method. Data were analyzed using noncompartmental methods, and multiple comparisons were performed on the log-transformed parameters, at steady state. Coadministration of AMDX with ZDV did not significantly change either of the plasma PK parameters or percent recovery in the urine of AMDX, DXG, or ZDV/GZDV. Larger studies with AMDX/ZDV, with a longer duration, are warranted.