Clinical Pharmacokinetics

, Volume 51, Issue 12, pp 809–822

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
Original Research Article

DOI: 10.1007/s40262-012-0012-y

Cite this article as:
Dumond, J.B., Nicol, M.R., Kendrick, R.N. et al. Clin Pharmacokinet (2012) 51: 809. doi:10.1007/s40262-012-0012-y

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.

Supplementary material

40262_2012_12_MOESM1_ESM.pdf (88 kb)
Supplementary material 1 (PDF 87 kb)

Copyright information

© Springer International Publishing Switzerland 2012

Authors and Affiliations

  • Julie B. Dumond
    • 1
  • Melanie R. Nicol
    • 1
  • Racheal N. Kendrick
    • 1
  • Samira M. Garonzik
    • 2
  • Kristine B. Patterson
    • 3
  • Myron S. Cohen
    • 3
  • Alan Forrest
    • 2
  • Angela D. M. Kashuba
    • 1
  1. 1.UNC Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.School of Pharmacy and Pharmaceutical SciencesState University of New York, University at BuffaloBuffaloUSA
  3. 3.School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations