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Population pharmacokinetics of tenofovir and tenofovir‐diphosphate in healthy women
Author(s) -
Burns Rebecca N.,
Hendrix Craig W.,
Chaturvedula Ayyappa
Publication year - 2015
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.461
Subject(s) - pharmacokinetics , bioavailability , medicine , population , tenofovir , crossover study , pharmacology , volume of distribution , lag time , absorption (acoustics) , human immunodeficiency virus (hiv) , immunology , biology , physics , alternative medicine , environmental health , pathology , acoustics , placebo , biological system
The objective of this analysis was to develop and qualify a population pharmacokinetic model describing plasma tenofovir (TFV) concentrations and tenofovir‐diphosphate (TFV‐DP) concentrations in peripheral blood mononuclear cell (PBMC) in healthy women volunteers from the MTN‐001 clinical trial, an open label 3‐way crossover study of oral tenofovir disoproxil fumarate 300 mg tablet, TFV 1% vaginal gel, or both. TFV pharmacokinetics were best described by a 2‐compartment, first‐order absorption/elimination model with absorption lag time. TFV was linked to PBMC TFV‐DP by first‐order uptake with first‐order elimination. An adherence adjustment was included to account for nonadherence by explicitly modeling a bioavailability parameter on the previous day's dose. The final model included weight as a covariate on central compartment volume (V c ) with estimates as follows: absorption rate constant (Ka) 9.79 h −1 , absorption lag time 0.5 hours, V c 385.71–2.16*(73‐WT(kg)), and apparent TFV clearance of 56.7 L/h ((K20 + K24)*V c ). TFV‐DP's half‐life was 53.3 hours. All diagnostic plots and bootstrap confidence intervals were acceptable. Model validation was conducted using simulations compared to data from the MTN‐001 oral + vaginal period and other clinical trial data. The resulting model closely predicted the disposition of TFV and TFV‐DP when compared to healthy participant data from another clinical trial.