Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis

Abstract

Objectives: To describe first dose and steady state antiretroviral drug exposure in the female genital tract.

Design: Non-blinded, single center, open-label pharmacokinetic study in HIV-infected women.

Method: Twenty-seven women initiating combination antiretroviral therapy underwent comprehensive blood plasma and cervicovaginal fluid sampling for drug concentrations during the first dose of antiretroviral therapy and at steady-state. Drug concentrations were measured by validated HPLC/UV or HPLC-MS/MS methods. Pharmacokinetic parameters were estimated for 11 drugs by non-compartmental analysis. Descriptive statistics and 95% confidence intervals were generated using Intercooled STATA Release 8.0 (Stata Corporation, College Station, Texas, USA).

Results: For all antiretroviral drugs, genital tract concentrations were detected rapidly after the first dose. Drugs were stratified according to the genital tract concentrations achieved relative to blood plasma. Median rank order of highest to lowest genital tract concentrations relative to blood plasma at steady state were: lamivudine (concentrations achieved were 411% greater than blood plasma), emtricitabine (395%), zidovudine (235%) tenofovir (75%), ritonavir (26%), didanosine (21%), atazanavir (18%), lopinavir (8%), abacavir (8%), stavudine (5%), and efavirenz (0.4%).

Conclusions: This is the first study to comprehensively evaluate antiretroviral drug exposure in the female genital tract. These findings support the use of lamivudine, zidovudine, tenofovir and emtricitabine as excellent pre-exposure/post-exposure prophylaxis (PrEP/PEP) candidates. Atazanavir and lopinavir might be useful agents for these applications due to favorable therapeutic indices, despite lower genital tract concentrations. Agents such as stavudine, abacavir, and efavirenz that achieve genital tract exposures less than 10% of blood plasma are less attractive PrEP/PEP candidates.

Fig. 1

(a) Mean (SE) pharmacokinetic profile of zidovudine (ZDV) over a 12 h dosing interval in blood plasma (BP) and genital tract (GT) at first dose and steady state. Subjects received 300 mg every 12 h. The solid line represents an extracellular target concentration previously suggested as efficacious in clinical studies [20,21]. (b) Mean (SE) pharmacokinetic profile of lamivudine (3TC) over a 24 h dosing interval in BP and GT at first dose and steady state. Subjects received 300 mg every 24 h. The solid line represents an extracellular target concentration previously suggested as efficacious in clinical studies [20,21]. (c) Mean (SE) pharmacokinetic profile of emtricitabine (FTC) over a 24 h dosing interval in BP and GT at first dose and steady state. Subjects received 200 mg every 24 h. No target concentration for clinical efficacy has been defined. (d) Mean (SE) pharmacokinetic profiles of tenofovir (TDF) over a 24 h dosing interval in BP and GT at first dose and steady state. Patients received 300 mg of TDF every 24 h. No target concentration for clinical efficacy has been defined. (e) Mean (SE) pharmacokinetic profile of atazanavir (ATV) over a 24 h dosing interval in BP and GT at first dose and steady state. Patient received 300 mg of ATV and 100 mg of ritonavir (RTV) every 24 h. The solid line represents the suggested clinical target concentration for ATV [22]. (f) Mean (SE) pharmacokinetic profile of lopinavir (LPV) over a 12 h dosing interval in BP and GT at first dose and steady state. Subjects received 400 mg of LPV and 100 mg of RTV every 12 h. The solid line represents a suggested clinical target concentration for LPV [22]. (g) Mean (SE) pharmacokinetic profile of efavirenz (EFV) over a 24 h dosing interval in BP and GT at first dose and steady state. Subjects received 600 mg of EFV every 24 h. The solid line represents a suggested clinical target concentration for EFV [22].

Fig. 1

(a) Mean (SE) pharmacokinetic profile of zidovudine (ZDV) over a 12 h dosing interval in blood plasma (BP) and genital tract (GT) at first dose and steady state. Subjects received 300 mg every 12 h. The solid line represents an extracellular target concentration previously suggested as efficacious in clinical studies [20,21]. (b) Mean (SE) pharmacokinetic profile of lamivudine (3TC) over a 24 h dosing interval in BP and GT at first dose and steady state. Subjects received 300 mg every 24 h. The solid line represents an extracellular target concentration previously suggested as efficacious in clinical studies [20,21]. (c) Mean (SE) pharmacokinetic profile of emtricitabine (FTC) over a 24 h dosing interval in BP and GT at first dose and steady state. Subjects received 200 mg every 24 h. No target concentration for clinical efficacy has been defined. (d) Mean (SE) pharmacokinetic profiles of tenofovir (TDF) over a 24 h dosing interval in BP and GT at first dose and steady state. Patients received 300 mg of TDF every 24 h. No target concentration for clinical efficacy has been defined. (e) Mean (SE) pharmacokinetic profile of atazanavir (ATV) over a 24 h dosing interval in BP and GT at first dose and steady state. Patient received 300 mg of ATV and 100 mg of ritonavir (RTV) every 24 h. The solid line represents the suggested clinical target concentration for ATV [22]. (f) Mean (SE) pharmacokinetic profile of lopinavir (LPV) over a 12 h dosing interval in BP and GT at first dose and steady state. Subjects received 400 mg of LPV and 100 mg of RTV every 12 h. The solid line represents a suggested clinical target concentration for LPV [22]. (g) Mean (SE) pharmacokinetic profile of efavirenz (EFV) over a 24 h dosing interval in BP and GT at first dose and steady state. Subjects received 600 mg of EFV every 24 h. The solid line represents a suggested clinical target concentration for EFV [22].