The Pharmacokinetics of Amprenavir, Zidovudine, and Lamivudine in the Genital Tracts of Men Infected with Human Immunodeficiency Virus Type 1 (AIDS Clinical Trials Group Study 850)

Abstract

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.

High Concentration of Raltegravir in Semen of HIV-Infected Men: Results from a Substudy of the EASIER-ANRS 138 Trial

“…Concentrations of nonnucleoside reverse transcriptase inhibitors (NNRTIs) in seminal plasma are consistently measurable, although lower than those in blood plasma (14,21). Penetration of PIs in semen is poor, and seminal concentrations of PIs seem to be dependent on the degree of protein binding, with the weakest-bound drugs (amprenavir and indinavir) having the highest concentrations (5,13,19,20,23). In contrast to those observed for PIs, NRTI seminal plasma concentrations are similar to or higher than concentrations in blood plasma (5,6,13,21).…”

Determining Seminal Plasma Human Immunodeficiency Virus Type 1 Load in the Context of Efficient Highly Active Antiretroviral Therapy

“…HIV shedding may continue for up to 2 years in a few patients and may be high enough for sexual transmission (18). The different rates at which HAART acts on the two compartments seems to be directly linked to the poor diffusion of some antiretroviral drugs in the male genital tract, as indicated by drug concentrations in semen (20,23,25,27,29) and to intracellular active drug concentrations that are too low (8). Somewhat surprisingly, there have been no reports of impaired HAART efficiency (14) or local selection of resistant HIV (9,10,12,13,18) despite poor local drug concentrations and residual HIV shedding.…”

Quantification of antiretroviral drugs for HIV-1 in the male genital tract: current data, limitations and implications for laboratory analysis

“…Drug transporter activity or inhibition of P-glycoprotein may be enhanced by the ritonovir (van Praag et al 2000). Amprenavir achieves higher levels in semen than ritonovir and saquinavir Pereira et al 2002), despite being 90% protein-bound in blood . This is another example where pharmacokinetics are inconsistent with the degree of observed drug penetration.…”

“…Partial validation of T20 assay in human plasma. Pereira et al (2002) Amprenavir, zidovudine and lamivudine…”