title: Combination Pod-Intravaginal Ring Delivers Antiretroviral Agents for HIV Prophylaxis: Pharmacokinetic Evaluation in an Ovine Model.
abstract: Preexposure prophylaxis (PrEP) against HIV using oral regimens based on the nucleoside reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF) has been effective to various degrees in multiple clinical trials, and the CCR5 receptor antagonist maraviroc (MVC) holds potential for complementary efficacy. The effectiveness of HIV PrEP is highly dependent on adherence. Incorporation of the TDF-MVC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase product adherence and efficacy compared with oral and vaginal gel formulations. A novel pod-IVR technology capable of delivering multiple drugs is described. The pharmacokinetics and preliminary local safety characteristics of a novel pod-IVR delivering a combination of TDF and MVC were evaluated in the ovine model. The device exhibited sustained release at controlled rates over the 28-day study and maintained steady-state drug levels in cervicovaginal fluids (CVFs). Dilution of CVFs during lavage sample collection was measured by ion chromatography using an inert tracer, allowing corrected drug concentrations to be measured for the first time. Median, steady-state drug levels in vaginal tissue homogenate were as follows: for tenofovir (TFV; in vivo hydrolysis product of TDF), 7.3 × 10(2) ng g(-1) (interquartile range [IQR], 3.0 × 10(2), 4.0 × 10(3)); for TFV diphosphate (TFV-DP; active metabolite of TFV), 1.8 × 10(4) fmol g(-1) (IQR, 1.5 × 10(4), 4.8 × 10(4)); and for MVC, 8.2 × 10(2) ng g(-1) (IQR, 4.7 × 10(2), 2.0 × 10(3)). No adverse events were observed. These findings, together with previous pod-IVR studies, have allowed several lead candidates to advance into clinical evaluation.
authors.affiliation: Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Moss
authors.affiliation: Auritec Pharmaceuticals, Inc., Pasadena, California, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Butkyavichene
authors.affiliation: Auritec Pharmaceuticals, Inc., Pasadena, California, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Churchman
authors.affiliation: Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Gunawardana
authors.affiliation: Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, USA.
authors.forename: Rob
authors.initials: R
authors.lastname: Fanter
authors.affiliation: Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, USA.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Miller
authors.affiliation: Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, USA.
authors.forename: Flora
authors.initials: F
authors.lastname: Yang
authors.affiliation: Preclinical Surgical Research Laboratory, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Jeremiah T
authors.initials: JT
authors.lastname: Easley
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Marzinke
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
authors.affiliation: Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, USA Auritec Pharmaceuticals, Inc., Pasadena, California, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Smith
authors.affiliation: Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, USA m.baum@oak-crest.org.
authors.forename: Marc M
authors.initials: MM
authors.lastname: Baum
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D003274:Contraceptive Devices, Female; D003510:Cyclohexanes / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics*; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D000077592:Maraviroc; D023421:Models, Animal; D011322:Primary Prevention; D012756:Sheep; D000068698:Tenofovir / Q000493:pharmacokinetics*; D014230:Triazoles / Q000493:pharmacokinetics*; D014621:Vagina / Q000737:chemistry* / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D003510:Cyclohexanes; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D014230:Triazoles; D000068698:Tenofovir; D000077592:Maraviroc