Lack of pharmacokinetic interaction between amdoxovir and reduced- and standard-dose zidovudine in HIV-1-infected individuals

Abstract

Amdoxovir (AMDX) inhibits HIV-1 containing the M184V/I mutation and is rapidly absorbed and deaminated to its active metabolite, beta-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.

FIG. 1.

Plasma concentrations (ng/ml; mean ± SD) of AMDX (open symbols) and DXG (closed symbols) by cohort following the administration of 500 mg of AMDX b.i.d. following the initial dose on day 1 (A) and following the day 10 dose (B). Subjects received AMDX alone (○) or with ZDV at 200 mg (▵) or 300 mg (□) b.i.d.

FIG. 2.

Plasma concentrations (ng/ml; mean ± SD) of ZDV on day 1 (A) and at steady state (B) by cohort. •, ZDV at 200 mg (n = 2); ▪, ZDV at 300 mg (n = 2); ▴, ZDV at 200 mg plus AMDX at 500 mg b.i.d. (n = 6); ▾, ZDV at 300 mg plus AMDX at 500 mg b.i.d. (n = 6).