Population Modeling Highlights Drug Disposition Differences Between Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate in the Blood and Semen

Clin Pharmacol Ther. 2019 Oct;106(4):821-830. doi: 10.1002/cpt.1464. Epub 2019 May 31.

Abstract

Understanding antiretroviral disposition in the male genital tract, a distinct viral compartment, can provide insight for the eradication of HIV. Population pharmacokinetic modeling was conducted to investigate the disposition of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine and their metabolites in blood and semen. Blood plasma and seminal plasma (SP) concentrations of tenofovir and emtricitabine were measured, as were tenofovir-diphosphate and emtricitabine-triphosphate concentrations in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells. Sequential compartmental modeling described drug disposition in blood and semen. Our modeling suggests slower elimination of apparent tenofovir-diphosphate PBMC and faster elimination of tenofovir SP after administration of TAF compared with TDF, likely reflecting flip-flop kinetics. Additionally, TAF metabolism to tenofovir appeared slower in semen compared with blood; however, SP elimination of TAF-derived tenofovir appeared faster than its blood plasma elimination. These findings provide valuable insight for further mechanistic study of cellular entry and drug metabolism in the male genital tract.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / pharmacokinetics
  • Adult
  • Anti-Retroviral Agents / pharmacokinetics
  • Cell Count / methods
  • Emtricitabine / pharmacokinetics*
  • HIV Infections* / blood
  • HIV Infections* / drug therapy
  • HIV-1 / drug effects*
  • Humans
  • Leukocytes, Mononuclear / pathology
  • Male
  • Metabolic Clearance Rate
  • Plasma / chemistry*
  • Semen / chemistry*
  • Tenofovir / pharmacokinetics*
  • Tissue Distribution

Substances

  • Anti-Retroviral Agents
  • Tenofovir
  • tenofovir alafenamide
  • Emtricitabine
  • Adenine