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

TitlePlasma and intracellular population pharmacokinetic analysis of tenofovir in HIV-1-infected patients.
Publication TypePublication
Year of Publication2011
AuthorsBaheti G, Kiser JJ, Havens PL, Fletcher CV
JournalAntimicrob Agents Chemother
Volume55
Issue11
Pagination5294-9
Date Published2011 Nov
ISSN1098-6596
KeywordsAdenine, Adolescent, Adult, Chromatography, Liquid, Female, Humans, Male, Middle Aged, Organophosphonates, Tandem Mass Spectrometry, Tenofovir, Young Adult
Abstract

<p>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.</p>

DOI10.1128/AAC.05317-11
Alternate JournalAntimicrob. Agents Chemother.
PubMed ID21896913
PubMed Central IDPMC3194996
Grant ListP01 AI074340 / AI / NIAID NIH HHS / United States
U01 HD040474 / HD / NICHD NIH HHS / United States
U01 HD040533 / HD / NICHD NIH HHS / United States
U01 HD 040474 / HD / NICHD NIH HHS / United States