Partial protection against multiple RT-SHIV162P3 vaginal challenge of rhesus macaques by a silicone elastomer vaginal ring releasing the NNRTI MC1220. Academic Article uri icon

Overview

abstract

  • OBJECTIVES: The non-nucleoside reverse transcriptase inhibitor MC1220 has potent in vitro activity against HIV type 1 (HIV-1). A liposome gel formulation of MC1220 has previously been reported to partially protect rhesus macaques against vaginal challenge with a simian HIV (SHIV). Here, we describe the pre-clinical development of an MC1220-releasing silicone elastomer vaginal ring (SEVR), including pharmacokinetic (PK) and efficacy studies in macaques. METHODS: In vitro release studies were conducted on SEVRs loaded with 400 mg of MC1220, using simulated vaginal fluid (SVF, n = 4) and 1 : 1 isopropanol/water (IPA/H(2)O, n = 4) as release media. For PK evaluation, SEVRs were inserted into adult female macaques (n = 6) for 30 days. Following a 1 week washout period, fresh rings were placed in the same animals, which were then challenged vaginally with RT-SHIV162P3 once weekly for 4 weeks. RESULTS: SEVRs released 1.66 and 101 mg of MC1220 into SVF and IPA/H(2)O, respectively, over 30 days, the differential reflecting the low aqueous solubility of the drug. In macaque PK studies, MC1220 was consistently detected in vaginal fluid (peak 845 ng/mL) and plasma (peak 0.91 ng/mL). Kaplan-Meier analysis over 9 weeks showed significantly lower infection rates for animals given MC1220-containing SEVRs than placebo rings (hazard ratio 0.20, P = 0.0037). CONCLUSIONS: An MC1220-releasing SEVR partially protected macaques from vaginal challenge. Such ring devices are a practical method for providing sustained, coitally independent protection against vaginal exposure to HIV-1.

publication date

  • October 28, 2012

Research

keywords

  • Antiviral Agents
  • Contraceptive Devices, Female
  • Drug Carriers
  • Pyrimidinones
  • Silicone Elastomers
  • Simian Acquired Immunodeficiency Syndrome
  • Simian Immunodeficiency Virus

Identity

PubMed Central ID

  • PMC3543122

Scopus Document Identifier

  • 84872396180

Digital Object Identifier (DOI)

  • 10.1093/jac/dks415

PubMed ID

  • 23109186

Additional Document Info

volume

  • 68

issue

  • 2