title: Sustained release of the CCR5 inhibitors CMPD167 and maraviroc from vaginal rings in rhesus macaques.
abstract: Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 μg/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ~10(6)-fold greater than the 50% inhibitory concentrations (IC(50)s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.
authors.affiliation: School of Pharmacy, Queen’s University Belfast, Belfast, United Kingdom. k.malcolm@qub.ac.uk
authors.forename: R Karl
authors.initials: RK
authors.lastname: Malcolm
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Veazey
authors.forename: Leslie
authors.initials: L
authors.lastname: Geer
authors.forename: Deborah
authors.initials: D
authors.lastname: Lowry
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fetherston
authors.forename: Diarmaid J
authors.initials: DJ
authors.lastname: Murphy
authors.forename: Peter
authors.initials: P
authors.lastname: Boyd
authors.forename: Ian
authors.initials: I
authors.lastname: Major
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Lara A
authors.initials: LA
authors.lastname: Doyle
authors.forename: Kelsi K
authors.initials: KK
authors.lastname: Rasmussen
authors.forename: Laurie
authors.initials: L
authors.lastname: Goldman
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ketas
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001706:Biopsy; D065100:CCR5 Receptor Antagonists; D002851:Chromatography, High Pressure Liquid; D003274:Contraceptive Devices, Female; D003510:Cyclohexanes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D005260:Female; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008137:Longitudinal Studies; D008253:Macaca mulatta; D000077592:Maraviroc; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000502:physiology; D014018:Tissue Distribution; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014621:Vagina / Q000187:drug effects / Q000821:virology; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; C480490:CMPD 167; D003510:Cyclohexanes; D003692:Delayed-Action Preparations; D011720:Pyrazoles; D014230:Triazoles; D017258:Medroxyprogesterone Acetate; D014633:Valine; D000077592:Maraviroc