Lack of in vitro-in vivo correlation for a UC781-releasing vaginal ring in macaques

Christopher McConville, James M Smith, Clare F McCoy, Priya Srinivasan, James Mitchell, Angela Holder, Ron A Otten, Salvatore Butera, Gustavo F Doncel, David R Friend, R Karl Malcolm

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


This study describes the preclinical development of a matrix-type silicone elastomer vaginal ring device designed to provide controlled release of UC781, a non-nucleoside reverse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities considered sufficient to maintain vaginal fluid concentrations at levels 82-860-fold higher than the in vitro IC50 (2.0 to 10.4 nM) and therefore potentially protect against mucosal transmission of HIV. The 100-mg UC781 rings were well tolerated in pig-tailed macaques, did not induce local inflammation as determined by cytokine analysis and maintained median concentrations in vaginal fluids of UC781 in the range of 0.27 to 5.18 mM during the course of the 28-day study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque pharmacokinetic studies revealed that 57 and 5 mg of UC781 was released, respectively. The pharmacokinetic analysis of a 100-mg UC781 vaginal ring in pig-tailed macaques showed poor in vivo-in vitro correlation, attributed to the very poor solubility of UC781 in vaginal fluid and resulting in a dissolution-controlled drug release mechanism rather than the expected diffusion-controlled mechanism.

Original languageEnglish
Pages (from-to)27-37
Number of pages11
JournalDrug delivery and translational research
Issue number1
Early online date14 Jan 2015
Publication statusPublished - Feb 2015


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