Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis.
OBJECTIVE
To describe first dose and steady state antiretroviral drug exposure in the female genital tract.


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


METHODS
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.
Dumond
Julie B
JB
School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina, USA.
Yeh
Rosa F
RF
Patterson
Kristine B
KB
Corbett
Amanda H
AH
Jung
Byung Hwa
BH
Rezk
Naser L
NL
Bridges
Arlene S
AS
Stewart
Paul W
PW
Cohen
Myron S
MS
Kashuba
Angela D M
AD
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D000284:Administration, Oral; D000328:Adult; D000480:Alkynes; D044966:Anti-Retroviral Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D000069446:Atazanavir Sulfate; D048588:Benzoxazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D003521:Cyclopropanes; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005260:Female; D005836:Genitalia, Female / Q000378:metabolism*; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D061466:Lopinavir; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D063065:Organophosphonates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000068698:Tenofovir; D015215:Zidovudine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
D000480:Alkynes; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D063065:Organophosphonates; D011725:Pyridines; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D061466:Lopinavir; D019259:Lamivudine; D015215:Zidovudine; D000069446:Atazanavir Sulfate; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; C098320:efavirenz