Impact of ring size and drug loading on the pharmacokinetics of a combination dapivirine-darunavir vaginal ring in cynomolgus macaques

Diarmaid J. Murphy, Delphine Desjardins, Peter Boyd, Nathalie Dereuddre-Bosquet, Lev Stimmer, Anna Caldwell, Roger Le Grande, Charles Kelly, Jens Van Roey, R. Karl Malcolm

Research output: Contribution to journalArticle

8 Citations (Scopus)
147 Downloads (Pure)

Abstract

This work investigates the impact of vaginal ring size and drug loading on the in vitro release, safety, ease of fit, and pharmacokinetics in cynomolgus macaques of matrix-type silicone elastomer vaginal rings containing a combination of the non-nucleoside reverse transcriptase inhibitor dapivirine and the protease inhibitor darunavir. Drug-free and drug-loaded vaginal rings having three different geometries were manufactured by reaction injection molding. In vitro drug release was assessed using both a solvent/water mixture and a vaginal fluid simulant. Macaques fitted with drug-free vaginal rings for 28 days were assessed by colposcopy, cytological evaluation of cervico-vaginal lavage and histological evaluation of tissue after ring removal. The 20 × 4.5 mm combination ring, deemed most appropriate for vaginal fit and comfort in the macaques, was evaluted for pharmacokinetics over 28 days. Substantial differences were observed in the in vitro release profiles between the three ring sizes. However, these differences were not manifest in vivo, where measured drug concentrations after 20 × 4.5 mm ring use were not significantly different from those reported previously with a 25 × 6 mm ring. These results suggest that ring placement and fit is an important species-specific study parameter that should be optimised prior to pharmacokinetic testing.
Original languageEnglish
Pages (from-to)300–308
Number of pages9
JournalInternational Journal of Pharmaceutics
Volume550
Early online date25 Aug 2018
DOIs
Publication statusEarly online date - 25 Aug 2018

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