Yan Li, Simon Zhou*, Matthew Hoffmann, Gondi Kumar and Maria Palmisano
Celgene Cooperation, Summit, NJ, USA
Introduction: Pomalidomide is a immunomodulatory drug with pleiotropic actions of cytotoxity against multiple myeloma cells, immunomodulatory and anti-angiogenic activity, that has been approved for the treatment of multiple myeloma. Pomalidomide has an asymmetric carbon center and exists as the optically active forms S (-) and R (+), and has been developed as a racemate. The aim of this analysis was to explore the pharmacokinetic (PK) disposition of two pomalidomide enantiomers based on racemate PK profile in humans, and enantiomer PK profiles in animals, and to evaluate the interaction of distinct enantiomer PK dispositions and their in vivo interconversion on plasma exposure to the two enantiomers.
Material and methods: PK Modeling were performed in NONMEM 7.2 to describe the observed PK data of S- and R-isomers in humans and monkeys accounting for respective species difference in enantiomer PK disposition and enantiomer interconversion on two enantiomer plasma exposure in humans and monkeys. Subsequent simulations were conducted to assess the interaction between isomer interconversion and distinct isomer elimination on plasma exposure to two isomers. Key measure of isomer interconversion rate relative to racemate elimination rate were derived and calibrated in determining potential difference to individual isomer plasma exposure.
Results: PK modeling based on a physiological plausible model with distinct PK dispositional parameters for two enantiomers and concurrent isomer intercoversion provided adequate fit for the S- and R-isomer observations in humans and monkeys. Modeling results showed that the in vivo elimination rate is 0.09 hr-1 which was lower than the R-/S- inter-conversion rate of 0.353 hr-1 in human. However, the in vivo elimination rate is 0.55 hr-1, and comparable/higher than the R-/S- inter-conversion rate of 0.223 hr-1 in monkeys. Simulation results demonstrated that the higher the ratio of the in vivo elimination to the inter-conversion, the larger the difference of PK exposures between R- and S- enantiomers.
Conclusions: This PK analysis demonstrated the utility and power of M&S in elucidating experimentally challenging and technically difficult issues, providing scientific rationale and eliminating the need for uninterruptable and costly studies.
Reference: PAGE 22 (2013) Abstr 2966 [www.page-meeting.org/?abstract=2966]
Poster: Other Modelling Applications