Author(s): Baheti G, Kiser JJ, Havens PL, Fletcher CV
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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.
This article was published in Antimicrob Agents Chemother
and referenced in Journal of Chromatography & Separation Techniques