title: Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis.
abstract: Orally administered anti-retroviral drugs show considerable promise for HIV/AIDS pre-exposure prophylaxis (PrEP). For the success of these strategies, pharmacokinetic (PK) data defining the optimal concentration of the drug needed for protection in relevant mucosal exposure sites is essential. Here we employed a humanized mouse model to derive comprehensive PK data on the HIV integrase inhibitor raltegravir (RAL), a leading PrEP drug candidate. Under steady state conditions following oral dosing, plasma and multiple mucosal tissues were sampled simultaneously. RAL exhibited higher drug exposure in mucosal tissues relative to that in plasma with one log higher exposure in vaginal and rectal tissue and two logs higher exposure in intestinal mucosa reflecting the trends seen in the human studies. These data demonstrate the suitability of RAL for HIV PrEP and validate the utility of humanized mouse models for deriving important preclinical PK-PD data.
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
authors.forename: Milena
authors.initials: M
authors.lastname: Veselinovic
authors.affiliation: Eshelman School of Pharmacy, NC, USA.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Yang
authors.affiliation: Eshelman School of Pharmacy, 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, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Remling-Mulder
authors.affiliation: Eshelman School of Pharmacy, NC, USA; School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA. Electronic address: akkina@colostate.edu.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Akkina
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009092:Mucous Membrane / Q000187:drug effects / Q000821:virology; D065129:Pre-Exposure Prophylaxis; D000068898:Raltegravir Potassium / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D019428:HIV Integrase Inhibitors; D000068898:Raltegravir Potassium
keywords: Mucosal tissue PK of raltegravir; PK–PD studies on raltegravir; Pharmacokinetics of raltegravir in hu-mice; Pre-Exposure Prophylaxis for HIV/AIDS; Raltegravir for HIV prevention