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.
From the aSchool of Pharmacy, University of North Carolina at Chapel Hill, North Carolina, USA
bCollege of Pharmacy, University of Houston, Texas, USA
cSchool of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
dBioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Seoul, South Korea.
Received 6 February, 2007
Revised 24 April, 2007
Accepted 27 April, 2007
Correspondence to Angela D.M. Kashuba, BScPharm, PharmD, DABCP, School of Pharmacy, University of North Carolina at Chapel Hill, 3318 Kerr Hall, CB, #7360, Chapel Hill, NC, USA. E-mail: firstname.lastname@example.org
This work was presented in part at the 13th Conference on Retroviruses and Opportunistic Infections.