Pharmacokinetic modelling of efavirenz, atazanavir, lamivudine and tenofovir in the female genital tract of HIV-infected pre-menopausal women

Julie B. Dumond, Melanie R. Nicol, Racheal N. Kendrick, Samira M. Garonzik, Kristine B. Patterson, Myron S. Cohen, Alan Forrest, Angela D M Kashuba

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Background and Objectives: A previously published study of antiretroviral pharmacokinetics in the female genital tract of HIV-infected women demonstrated differing degrees of female genital tract penetration among antiretrovirals. These blood plasma (BP) and cervicovaginal fluid (CVF) data were co-modelled for four antiretrovirals with varying CVF exposures. Methods: Six paired BP and CVF samples were collected over 24 h, and antiretroviral concentrations determined using validated liquid chromatography (LC) with UV detection or LC-mass spectrometry analytical methods. For each antiretroviral, a BP model was fit using Bayesian estimation (ADAPT5), followed by addition of a CVF model. The final model was chosen based on graphical and statistical output, and then non-linear mixed-effects modelling using S-ADAPT was performed. Population mean parameters and their variability are reported. Model-predicated area under the concentration-time curve during the dosing interval (AUCτ) and exposure ratios of CVF AUCτ:BP AUCτ were calculated for each drug. Results: The base model uses first-order absorption with a lag time, a two-compartment model, and a series of transit compartments that transfer the drug from BP to CVF. Protein-unbound drug transfers into CVF for efavirenz and atazanavir; total drug transfers for lamivudine and tenofovir. CVF follows a one-compartment model for efavirenz and atazanavir, and a two-compartment model for lamivudine and tenofovir. As expected, inter-individual variability was high. Model-predicted CVF AUC τ:BP AUCτ ratios are consistent with published results. Conclusions: This is the first pharmacokinetic modelling of antiretroviral disposition in BP and CVF. These models will be further refined with tissue data, and used in clinical trials simulations to inform future studies of HIV pre-exposure prophylaxis in women.

Original languageEnglish (US)
Pages (from-to)809-822
Number of pages14
JournalClinical Pharmacokinetics
Volume51
Issue number12
DOIs
StatePublished - Dec 2012

Bibliographical note

Funding Information:
Conflict of interest A.D.M. Kashuba has received research funding and speaking honoraria from Bristol-Myers Squibb, Merck, Gilead and GlaxoSmithKline. K.B. Patterson has received research funding from GlaxoSmithKline. The other authors have no conflicts of interest that are directly relevant to the content of this study.

Funding Information:
Acknowledgments The authors wish to thank the participating subjects, as well as the staff of the UNC Healthcare Infectious Disease Clinic for their assistance with recruitment. We also thank the nurses of the UNC CTRC for their assistance in conducting study visits. This work was presented in part at the 13th International Workshop on Clinical Pharmacology of HIV Therapy, 16–18 April 2012, Barcelona, Spain. Financial support for this work was provided by the UNC Center for AIDS Research (5P30AI050410-13—J.B. Dumond, K.B. Patterson, A.D.M. Kashuba), the NC TraCS Institute (UL1RR025747—J.B. Dumond) and the National Institute of Allergy and Infectious Diseases (K23AI093156—J.B. Du-mond; K23AI077355-KBP; K23AI54980—A.D.M. Kashuba; U01AI0 95031—A.D.M. Kashuba). These funding sources provided salary support and funds for research conduct, but did not have any input into study design, study analysis or reporting of study results.

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