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

被引:21
作者
Dumond, Julie B. [1 ]
Nicol, Melanie R. [1 ]
Kendrick, Racheal N. [1 ]
Garonzik, Samira M. [2 ]
Patterson, Kristine B. [3 ]
Cohen, Myron S. [3 ]
Forrest, Alan [2 ]
Kashuba, Angela D. M. [1 ]
机构
[1] Univ N Carolina, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 USA
[2] SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Buffalo, NY 14260 USA
[3] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA
关键词
PERFORMANCE LIQUID-CHROMATOGRAPHY; REVERSE-TRANSCRIPTASE INHIBITORS; POPULATION PHARMACOKINETICS; ANTIRETROVIRAL THERAPY; HUMAN PLASMA; QUANTIFICATION; TYPE-1; DRUGS;
D O I
10.1007/s40262-012-0012-y
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 (ADAPTS), 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 (AUC(tau)) and exposure ratios of CVF AUC(tau):BP AUC(tau) 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(tau):BP AUC(tau) 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 preexposure prophylaxis in women.
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收藏
页码:809 / 822
页数:14
相关论文
共 41 条
  • [1] NEW LOOK AT STATISTICAL-MODEL IDENTIFICATION
    AKAIKE, H
    [J]. IEEE TRANSACTIONS ON AUTOMATIC CONTROL, 1974, AC19 (06) : 716 - 723
  • [2] [Anonymous], EP FULL US PRESCR IN
  • [3] [Anonymous], 2007, AIDS
  • [4] [Anonymous], VIR FULL US PRESCR I
  • [5] [Anonymous], SUST EF FULL US PRES
  • [6] [Anonymous], AM C PHARM APR 4 7 S
  • [7] [Anonymous], REYAT AT FULL US PRE
  • [8] Ways to fit a PK model with some data below the quantification limit
    Beal, SL
    [J]. JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, 2001, 28 (05) : 481 - 504
  • [9] Performance and Robustness of the Monte Carlo Importance Sampling Algorithm Using Parallelized S-ADAPT for Basic and Complex Mechanistic Models
    Bulitta, Jurgen B.
    Landersdorfer, Cornelia B.
    [J]. AAPS JOURNAL, 2011, 13 (02): : 212 - 226
  • [10] Development of a New Pre- and Post-Processing Tool (SADAPT-TRAN) for Nonlinear Mixed-Effects Modeling in S-ADAPT
    Bulitta, Jurgen Bernd
    Bingoelbali, Ayhan
    Shin, Beom Soo
    Landersdorfer, Cornelia Barbara
    [J]. AAPS JOURNAL, 2011, 13 (02): : 201 - 211