title: Distinct Pharmacodynamic Activity of Rilpivirine in Ectocervical and Colonic Explant Tissue.
abstract: A long-acting injectable form of rilpivirine (RPV) is being evaluated in clinical trials for the prevention of HIV infection. Preclinical testing was undertaken to define RPV pharmacokinetic (PK) and pharmacodynamic (PD) activities in ectocervical and colonic tissue treated in vitro Tenfold dilutions of RPV were added to the basolateral medium of polarized ectocervical and colonic explant tissues. To half the explants, HIV-1BaL was applied to the apical tissue surface. After culture overnight, all the explants were washed and the RPV in the explants not exposed to HIV was quantified using a validated liquid chromatography-mass spectrometry assay. For efficacy, explants exposed to HIV remained in culture, and supernatants were collected to assess viral replication using a p24 enzyme-linked immunosorbent assay. The data were log10 transformed, and PK/PD correlations were determined using GraphPad Prism and SigmaPlot software. The application of RPV to the basolateral medium at 10 μM and 1 μM was effective in protecting ectocervical and colonic tissues, respectively, from HIV infection. When the RPV in paired ectocervical and colonic explant tissues was quantified, significant inverse linear correlations (P < 0.001) between p24 and RPV concentrations were obtained; more viral replication was noted at lower drug levels. Using a maximum effect model, RPV concentrations of 271 nM in ectocervical tissue and 45 nM in colonic tissue were needed to achieve a 90% effective concentration (EC90). These data demonstrate that RPV can suppress HIV infection in mucosal tissue but that higher levels of RPV are needed in female genital tract tissue than in gastrointestinal tract tissue for protection.
authors.affiliation: School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA cdezzutti@mwri.magee.edu.
authors.forename: Charlene S
authors.initials: CS
authors.lastname: Dezzutti
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Else
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Yandura
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Cory
authors.initials: C
authors.lastname: Shetler
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Russo
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.affiliation: School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: McGowan
mesh_terms: D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity; D006801:Humans; D000068696:Rilpivirine / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012984:Software
chemical_list: D019380:Anti-HIV Agents; D000068696:Rilpivirine