Sustained release of the CCR5 inhibitors CMPD167 and maraviroc from vaginal rings in rhesus macaques.

TitleSustained release of the CCR5 inhibitors CMPD167 and maraviroc from vaginal rings in rhesus macaques.
Publication TypeJournal Article
Year of Publication2012
AuthorsR Malcolm K, Veazey RS, Geer L, Lowry D, Fetherston SM, Murphy DJ, Boyd P, Major I, Shattock RJ, Klasse PJohan, Doyle LA, Rasmussen KK, Goldman L, Ketas TJ, Moore JP
JournalAntimicrob Agents Chemother
Date Published2012 May
KeywordsAdministration, Intravaginal, Animals, Anti-HIV Agents, Biopsy, CCR5 Receptor Antagonists, Chromatography, High Pressure Liquid, Contraceptive Devices, Female, Cyclohexanes, Delayed-Action Preparations, Female, HIV Infections, HIV-1, Humans, Longitudinal Studies, Macaca mulatta, Medroxyprogesterone Acetate, Pyrazoles, Simian Acquired Immunodeficiency Syndrome, Simian immunodeficiency virus, Tissue Distribution, Triazoles, Vagina, Valine, Virus Internalization

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.

Alternate JournalAntimicrob. Agents Chemother.
PubMed ID22330914
PubMed Central IDPMC3346641
Grant ListU19AI76982 / AI / NIAID NIH HHS / United States

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