Demonstration of in vitro-in vivo relationship (IVIVR) and virtual bioequivalence (VBE) between progesterone intravaginal rings using physiologically based pharmacokinetic (PBPK) modelling.

The vaginal route of administration enables convenient local and systemic drug delivery with the avoidance of hepatic first-pass metabolism. Considering the clinical advantages of vaginal delivery, development of physiologically based pharmacokinetic (PBPK) models of vaginal absorption to inform drug and formulation development is deemed valuable. The present study employs the Mechanistic Vaginal Absorption & Metabolism (MechVAM) model implemented in Simcyp Simulator to simulate plasma concentrations after the local administration of progesterone vaginal gel and ring formulations. The study details the development and validation of an in vitro-in vivo relationship (IVIVR) used to simulate the in vivo release from measured in vitro release profiles. Further, virtual bioequivalence (VBE) from two different clinical trials was evaluated using the validated IVIVR to compare with actual bioequivalence (BE) clinical trial results. VBE testing was also leveraged to establish in vitro release safe space limits. In conclusion, PBPK can support IVIVR development and alternative BE methodologies with reduced human testing. The validated vaginal absorption model described here can also support post approval changes provided the in vitro release of modified formulations falls within the established in vitro dissolution safe space limits of -7.36% and +9.40% mg/day release on day 1, 2 and 7 respectively.