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

R. Karl Malcolm, Ronald S. Veazey, Leslie Geer, Deborah Lowry, Susan M. Fetherston, Diarmaid J. Murphy, Peter Boyd, Ian Major, Robin J. Shattock, Per J. Klasse, Lara A. Doyle, Kelsi K. Rasmussen, Laurie Goldman, Thomas J. Ketas, John P. Moore

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)2251-2258
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Issue number5
Early online date13 Feb 2012
Publication statusPublished - May 2012


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