Plasma and intracellular population pharmacokinetic analysis of tenofovir in HIV-1-infected patients

Abstract

The relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n = 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h(-1); apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (E(max)), the TFV concentration producing 50% of E(max) (EC(50)), and the intracellular elimination rate constant (k(out)) of 300 fmol/10(6) cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h(-1), respectively. The estimated k(out) gave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.

Fig. 1.

Schematic presentation of a two-compartment open pharmacokinetic model coupled with a stimulatory indirect pharmacodynamic response model. Cp, plasma TFV concentration; k_a, first-order rate constant for TFV absorption; k_in, apparent zero-order rate constant for the production of intracellular TFV-DP concentration; k_out, first-order rate constant for the loss of TFV-DP; E_max, maximal intracellular concentration; EC₅₀, plasma TFV concentration that produces 50% of E_max.

Fig. 2.

Plasma concentrations of TFV and the visual predictive check (VPC) for the final model for plasma TFV.

Fig. 3.

Intracellular concentrations of TFV-DP and the visual predictive check (VPC) for the final model for intracellular TFV-DP.