title: HIV pre-exposure prophylaxis: mucosal tissue drug distribution of RT inhibitor Tenofovir and entry inhibitor Maraviroc in a humanized mouse model.
abstract: Pre-exposure prophylaxis (PrEP) strategies utilizing anti-retroviral drugs show considerable promise for HIV prevention. However there is insufficient pharmacokinetic (PK) data on drug concentrations required for protection at the relevant mucosal tissues where the infection is initiated. Here we evaluated the utility of a humanized mouse model to derive PK data on two leading drugs, the RT inhibitor Tenofovir (TFV) and CCR5 inhibitor Maraviroc (MVC). Following oral dosing, both the drugs and the intracellular active TFV-diphosphate could be detected in vaginal, rectal and intestinal tissues. The drug exposures (AUC₂₄ h) were found to be higher in vaginal tissue compared to plasma with even higher levels detected in rectal and intestinal tissues. The overall trends of drug concentrations seen in humanized mice reflect those seen in the human thus establishing the utility of this model complementing the present non-human primate (NHP) models for future pre-clinical evaluations of promising HIV PrEP drug candidates.
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Milena
authors.initials: M
authors.lastname: Veselinovic
authors.affiliation: Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Yang
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: LeCureux
authors.affiliation: Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Sykes
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Remling-Mulder
authors.affiliation: Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA; School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Angela D M
authors.initials: ADM
authors.lastname: Kashuba
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA. Electronic address: akkina@colostate.edu.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Akkina
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003510:Cyclohexanes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D000077592:Maraviroc; D051379:Mice; D009092:Mucous Membrane / Q000378:metabolism* / Q000821:virology; D063065:Organophosphonates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D065129:Pre-Exposure Prophylaxis; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage; D000068698:Tenofovir; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D003510:Cyclohexanes; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; D000068698:Tenofovir; D000225:Adenine; D000077592:Maraviroc
keywords: Anti-retroviral drug pharmacokinetics in humanized mice; HIV pre-exposure prophylaxis in hu-mice; Humanized mice for HIV PrEP PK studies; Tenofovir and maraviroc phamacokinetics in hu-mice
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