Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues

J Antimicrob Chemother. 2017 Jun 1;72(6):1731-1740. doi: 10.1093/jac/dkx064.

Abstract

Objectives: Tenofovir alafenamide, a prodrug of tenofovir, produces higher PBMC concentrations of tenofovir diphosphate (tenofovir-dp) than tenofovir disoproxil fumarate. To understand tenofovir alafenamide's mucosal tissue distribution and its implications for pre-exposure prophylaxis, we characterized tenofovir-dp in female genital tract (FGT) and lower gastrointestinal (GI) tissues.

Methods: Healthy seronegative women were given 5, 10 or 25 mg of tenofovir alafenamide ( n = 8/group). Each participant provided plasma, PBMC and cervical, vaginal and rectal tissue samples over 14 days. Plasma, cell lysate and tissue homogenate concentrations were analysed by LC-MS/MS. Dose proportionality was declared in plasma and PBMCs if the natural log AUC versus natural log dose regression line 90% CI was within 0.57-1.43. In vitro tenofovir-dp formation was assessed in PBMCs and ectocervical (Ect1/E6E7) and vaginal (VK2/E6E7) cells incubated in 0.5 and 10 μM tenofovir alafenamide or tenofovir. clinicaltrials.gov: NCT02357602.

Results: Following single doses of 5, 10 and 25 mg, median (IQR) tenofovir plasma AUC 0-14 days was 52.8 (49.5-59.6), 78.1 (68.2-86.9) and 169.7 (131.2-211.4) ng·h/mL and tenofovir-dp PBMC AUC 0-14 days was 2268 (1519-4090), 4584 (3113-5734) and 9306 (6891-10785) fmol·h/10 6 cells, respectively. Tenofovir was quantifiable in 52% and 92% of FGT and GI tissues, whereas tenofovir-dp was quantifiable in only 5% and 19% of FGT and GI tissues, respectively. Plasma tenofovir and PBMC tenofovir-dp were dose proportional (90% CI = 0.87-1.15 and 0.62-1.02, respectively). In vitro tenofovir-dp was 1.7-17-fold higher in epithelial cells than PBMCs.

Conclusions: After tenofovir alafenamide dosing in vivo , tenofovir-dp was unquantifiable in most tissues (91%) although cervical and vaginal epithelial cells efficiently formed tenofovir-dp from tenofovir alafenamide in vitro . These findings warrant further investigation of tenofovir alafenamide's pharmacology.

Publication types

  • Clinical Trial

MeSH terms

  • Adenine / administration & dosage
  • Adenine / analogs & derivatives*
  • Adenine / blood
  • Adenine / metabolism
  • Adenine / pharmacokinetics
  • Adult
  • Cervix Uteri / chemistry
  • Cervix Uteri / cytology
  • Cervix Uteri / metabolism
  • Drug Administration Schedule
  • Epithelial Cells / chemistry
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Female
  • Gastrointestinal Tract / chemistry
  • Gastrointestinal Tract / metabolism
  • Humans
  • Intestinal Mucosa / metabolism*
  • Leukocytes, Mononuclear / chemistry
  • Leukocytes, Mononuclear / metabolism
  • Middle Aged
  • Mucous Membrane / chemistry
  • Mucous Membrane / metabolism*
  • Organophosphates / blood
  • Organophosphates / metabolism
  • Organophosphates / pharmacokinetics*
  • Pre-Exposure Prophylaxis
  • Rectum / chemistry
  • Rectum / cytology
  • Rectum / metabolism
  • Tissue Distribution
  • Vagina / chemistry
  • Vagina / metabolism
  • Young Adult

Substances

  • Organophosphates
  • tenofovir diphosphate
  • GS-7340
  • Adenine

Associated data

  • ClinicalTrials.gov/NCT02357602