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

Antimicrob Agents Chemother. 2011 Nov;55(11):5294-9. doi: 10.1128/AAC.05317-11. Epub 2011 Sep 6.


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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / blood
  • Adenine / pharmacokinetics
  • Adolescent
  • Adult
  • Chromatography, Liquid
  • Female
  • Humans
  • Male
  • Middle Aged
  • Organophosphonates / blood*
  • Organophosphonates / pharmacokinetics*
  • Tandem Mass Spectrometry
  • Tenofovir
  • Young Adult


  • Organophosphonates
  • Tenofovir
  • Adenine