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 (Vc) with estimates as follows: absorption rate constant (Ka) 9.79 h-1, absorption lag time 0.5 hours, Vc 385.71-2.16∗(73-WT(kg)), and apparent TFV clearance of 56.7 L/h ((K20 + K24)∗Vc). 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.
- population pharmacokinetics