title: Partial protection against multiple RT-SHIV162P3 vaginal challenge of rhesus macaques by a silicone elastomer vaginal ring releasing the NNRTI MC1220.
abstract: OBJECTIVE
  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.
authors.affiliation: School of Pharmacy,  Queen's University Belfast, Belfast BT9 7BL,  UK.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fetherston
authors.forename: Leslie
authors.initials: L
authors.lastname: Geer
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Veazey
authors.forename: Laurie
authors.initials: L
authors.lastname: Goldman
authors.forename: Diarmaid J
authors.initials: DJ
authors.lastname: Murphy
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ketas
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Sylvain
authors.initials: S
authors.lastname: Blois
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: R Karl
authors.initials: RK
authors.lastname: Malcolm
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001826:Body Fluids / Q000737:chemistry; D003274:Contraceptive Devices, Female; D004337:Drug Carriers; D005260:Female; D005464:Fluorobenzenes; D006801:Humans; D008253:Macaca mulatta; D010949:Plasma / Q000737:chemistry; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012826:Silicone Elastomers / Q000008:administration & dosage*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity*; D016896:Treatment Outcome; D014621:Vagina / Q000737:chemistry
chemical_list: C506288:6-(1-(2,6-difluorophenyl)ethyl)-2-(dimethylamino)-5-methylpyrimidin-4(3H)-one; D000998:Antiviral Agents; D004337:Drug Carriers; D005464:Fluorobenzenes; D011744:Pyrimidinones; D012826:Silicone Elastomers