title: A Translational Pharmacology Approach to Predicting Outcomes of Preexposure Prophylaxis Against HIV in Men and Women Using Tenofovir Disoproxil Fumarate With or Without Emtricitabine.
abstract: BACKGROUND
  A novel translational pharmacology investigation was conducted by combining an in vitro efficacy target with mucosal tissue pharmacokinetic (PK) data and mathematical modeling to determine the number of doses required for effective human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP).
  
  
  METHODS
  A PK/pharmacodynamic (PD) model was developed by measuring mucosal tissue concentrations of tenofovir, emtricitabine, their active metabolites (tenofovir diphosphate [TFVdp] and emtricitabine triphosphate [FTCtp], respectively), and competing endogenous nucleotides (dATP and dCTP) in 47 healthy women. TZM-bl and CD4(+) T cells were used to identify 90% effective concentration (EC90) ratios of TFVdp to dATP and FTCtp to dCTP (alone and in combination) for protection against HIV. Monte-Carlo simulations were then performed to identify minimally effective dosing strategies to protect lower female genital tract and colorectal tissues.
  
  
  RESULTS
  The colorectal TFVdp concentration was 10 times higher than that in the lower female genital tract, whereas concentrations of endogenous nucleotides were 7-11 times lower. Our model predicted that ≥98% of the population achieved protective mucosal tissue exposure by the third daily dose of tenofovir disoproxil fumarate plus emtricitabine. However, a minimum adherence to 6 of 7 doses/week (85%) was required to protect lower female genital tract tissue from HIV, while adherence to 2 of 7 doses/week (28%) was required to protect colorectal tissue.
  
  
  CONCLUSIONS
  This model is predictive of recent PrEP trial results in which 2-3 doses/week was 75%-90% effective in men but ineffective in women. These data provide a novel approach for future PrEP investigations that can optimize clinical trial dosing strategies.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina-Chapel Hill.
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, employee at the time the work was done.
authors.forename: Kuo H
authors.initials: KH
authors.lastname: Yang
authors.affiliation: School of Medicine.
authors.forename: Heather M A
authors.initials: HM
authors.lastname: Prince
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina-Chapel Hill.
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-Chapel Hill.
authors.forename: Nicole
authors.initials: N
authors.lastname: White
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina-Chapel Hill.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Malone
authors.affiliation: School of Medicine.
authors.forename: Evan S
authors.initials: ES
authors.lastname: Dellon
authors.affiliation: School of Medicine.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Madanick
authors.affiliation: School of Medicine.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Shaheen
authors.affiliation: Gillings School of Global Public Health.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hudgens
authors.affiliation: Gillings School of Global Public Health.
authors.forename: Jacob
authors.initials: J
authors.lastname: Wulff
authors.affiliation: School of Medicine.
authors.forename: Kristine B
authors.initials: KB
authors.lastname: Patterson
authors.affiliation: Virology, Immunology, and Microbiology Core, UNC Center for AIDS Research, University of North Carolina-Chapel Hill.
authors.forename: Julie A E
authors.initials: JA
authors.lastname: Nelson
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina-Chapel Hill.
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D000068679:Emtricitabine / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D005544:Forecasting; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D009518:New York; D065129:Pre-Exposure Prophylaxis / Q000639:trends; D000068698:Tenofovir / Q000494:pharmacology* / Q000627:therapeutic use*; D057170:Translational Research, Biomedical; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000068698:Tenofovir; D000068679:Emtricitabine
keywords: HIV; antiretroviral; dose response; population pharmacokinetics-pharmacodynamics; preexposure prophylaxis; quantitative pharmacology; translational medicine