p16 INK4a , a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV-Infected Subjects

CPT Pharmacometrics Syst Pharmacol. 2017 Feb;6(2):120-127. doi: 10.1002/psp4.12150. Epub 2016 Dec 26.

Abstract

The goal of this study was to explore the relationships between tenofovir (TFV) and emtricitabine (FTC) disposition and markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression. Chronologic age is often explored in population pharmacokinetic (PK) analyses, and can be uninformative in capturing the impact of aging on physiology, particularly in human immunodeficiency virus (HIV)-infected patients. Ninety-one HIV-infected participants provided samples to quantify plasma concentrations of TFV/FTC, as well as peripheral blood mononuclear cell (PBMC) samples for intracellular metabolite concentrations; 12 participants provided 11 samples, and 79 participants provided 4 samples, over a dosing interval. Nonlinear mixed effects modeling of TFV/FTC and their metabolites suggests a relationship between TFV/FTC metabolite clearance (CL) from PBMCs and the expression of p16INK4a , a marker of cellular senescence. This novel approach to quantifying the influence of aging on PKs provides rationale for further work investigating the relationships between senescence and nucleoside phosphorylation and transport.

Publication types

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

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / pharmacokinetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Emtricitabine / administration & dosage
  • Emtricitabine / pharmacokinetics*
  • Female
  • HIV Infections / drug therapy
  • HIV Infections / genetics
  • HIV Infections / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Nonlinear Dynamics
  • Tenofovir / administration & dosage*
  • Tenofovir / pharmacology
  • Young Adult

Substances

  • Anti-HIV Agents
  • Cyclin-Dependent Kinase Inhibitor p16
  • P16 protein, human
  • Tenofovir
  • Emtricitabine