ABSTRACT
We compared seminal plasma pharmacokinetic data for the investigational amprenavir prodrug GW433908 with those for amprenavir and an amprenavir-ritonavir combination regimen. All 3 regimens resulted in detectable blood plasma and seminal plasma concentrations of amprenavir. The majority of these concentrations were greater than the plasma protein-corrected 50% inhibitory concentration for wild-type human immunodeficiency virus type 1.
Subject(s)
Anti-HIV Agents/blood , HIV Infections/blood , Organophosphates , Sulfonamides/blood , Adult , Carbamates , Chemistry, Pharmaceutical , Furans , HIV Protease Inhibitors/blood , HIV-1/drug effects , Humans , Male , Prodrugs/pharmacokinetics , Ritonavir/blood , Semen/metabolismABSTRACT
The AIDS Clinical Trials Group Study 850 (ACTG 850) evaluated the penetration of zidovudine (ZDV), lamivudine (3TC), and amprenavir (APV), given alone and in combination with the 2 nucleoside analogues, into the male genital tract, because these factors may affect human immunodeficiency virus (HIV) type 1 suppression and transmission. Nineteen men receiving APV monotherapy and 12 men receiving triple therapy donated blood plasma (BP) and seminal plasma (SP) during therapy. Paired SP and BP were used to calculate compartmental concentration ratios. APV SP concentrations were consistently lower than BP concentrations, ZDV SP concentrations approximated BP concentrations early but became greater later in the dosing interval, and 3TC SP concentrations were substantially greater than BP concentrations throughout. Observed SP concentrations plotted with population BP concentration-time curves confirmed these findings, suggesting that passive diffusion (APV), slowed elimination (ZDV), and either active accumulation and/or inhibition of elimination (3TC) are responsible for SP concentrations of these agents. The antiretroviral effect of APV monotherapy was related to APV concentrations.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Genitalia, Male/metabolism , HIV Infections/metabolism , HIV-1 , Lamivudine/pharmacokinetics , Sulfonamides/pharmacokinetics , Zidovudine/pharmacokinetics , Adult , Anti-HIV Agents/blood , Carbamates , Drug Therapy, Combination , Furans , HIV Infections/drug therapy , Humans , Lamivudine/blood , Male , RNA, Viral/blood , Semen/chemistry , Statistics, Nonparametric , Sulfonamides/blood , Zidovudine/bloodABSTRACT
A HPLC-MS-MS method to measure amprenavir in human seminal plasma has been developed and validated. The procedure uses stable, isotopically labeled 13C6-amprenavir as an internal standard and 100 microl of sample. The method is accurate (bias less than or equal to 7.2%) and precise (within- and between-day RSDs less than or equal to 4.2%) over the dynamic range of 30-4,000 ng/ml. Recently, this simple and sensitive method was used to determine amprenavir concentrations in seminal samples collected from HIV-1 positive subjects receiving amprenavir antiretroviral therapy as part of a multicenter clinical trial.
