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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

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 re- verse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities consid- ered 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 trans- mission 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 con- centrations 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 mecha- nism rather than the expected diffusion-controlled mechanism.
Original languageEnglish
Pages (from-to)27-37
Number of pages11
JournalDrug Delivery and Translational Research
Volume5
Issue number1
Early online date14 Jan 2015
DOIs
Publication statusPublished - Feb 2015

Keywords

  • UC781
  • Antiretroviral
  • Vaginal ring
  • HIV microbicide
  • In vivo–in vitro correlation

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