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Pharmacokinetic Modelling of Efavirenz, Atazanavir, Lamivudine and Tenofovir in the Female Genital Tract of HIV-Infected Pre-Menopausal Women

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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 AUCτ: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.

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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. Dumond; K23AI077355-KBP; K23AI54980—A.D.M. Kashuba; U01AI095031—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.

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.

Author contributions

J.B. Dumond: data collection, data analysis, including the original publication and current modelling applications, primary author of the original and current manuscript. M.R. Nicol: data analysis of atazanavir, critical review of the manuscript. R.N. Kendrick: data analysis of lamivudine, critical review of the manuscript. S.M. Garonzik: data analysis of the current modelling applications, critical review of the manuscript. K.B. Patterson: data collection, critical review of the original and current manuscript. M.S. Cohen: conceptual design of original study, critical review of the original and current manuscript. A. Forrest: data analysis of the current modelling applications, critical review of the manuscript. A.D.M. Kashuba: conceptual design of original study, data collection, data analysis of the original publication, funding of the original study, critical review of the original and current manuscript.

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Authors and Affiliations

  1. UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 3320 Kerr Hall, CB 7569, Chapel Hill, NC, 27599-7569, USA

    Julie B. Dumond, Melanie R. Nicol, Racheal N. Kendrick & Angela D. M. Kashuba

  2. School of Pharmacy and Pharmaceutical Sciences, State University of New York, University at Buffalo, Buffalo, NY, USA

    Samira M. Garonzik & Alan Forrest

  3. School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Kristine B. Patterson & Myron S. Cohen

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  1. Julie B. Dumond
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Correspondence to Julie B. Dumond.

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Dumond, J.B., Nicol, M.R., Kendrick, R.N. et al. Pharmacokinetic Modelling of Efavirenz, Atazanavir, Lamivudine and Tenofovir in the Female Genital Tract of HIV-Infected Pre-Menopausal Women. Clin Pharmacokinet 51, 809–822 (2012). https://doi.org/10.1007/s40262-012-0012-y

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