title: Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Mackenzie L
authors.initials: ML
authors.lastname: Cottrell
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Katy L
authors.initials: KL
authors.lastname: Garrett
authors.affiliation: School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Heather M A
authors.initials: HMA
authors.lastname: Prince
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Sykes
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Schauer
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Cindi W
authors.initials: CW
authors.lastname: Emerson
authors.affiliation: School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Peery
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Rooney
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: McCallister
authors.affiliation: School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Gay
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Angela D M
authors.initials: ADM
authors.lastname: Kashuba
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D000328:Adult; D000409:Alanine; D002584:Cervix Uteri / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D004334:Drug Administration Schedule; D004847:Epithelial Cells / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D041981:Gastrointestinal Tract / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000378:metabolism; D008875:Middle Aged; D009092:Mucous Membrane / Q000737:chemistry / Q000378:metabolism*; D010755:Organophosphates / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D065129:Pre-Exposure Prophylaxis; D012007:Rectum / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D000068698:Tenofovir / Q000031:analogs & derivatives; D014018:Tissue Distribution; D014621:Vagina / Q000737:chemistry / Q000378:metabolism; D055815:Young Adult
chemical_list: D010755:Organophosphates; C583447:tenofovir diphosphate; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine