PT - JOURNAL ARTICLE AU - Yan Li AU - Simon Zhou AU - Matthew Hoffmann AU - Gondi Kumar AU - Maria Palmisano TI - Modeling and Simulation to Probe the Pharmacokinetic Disposition of Pomalidomide <em>R</em>- and <em>S</em>-Enantiomers AID - 10.1124/jpet.114.215251 DP - 2014 Aug 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 265--272 VI - 350 IP - 2 4099 - http://jpet.aspetjournals.org/content/350/2/265.short 4100 - http://jpet.aspetjournals.org/content/350/2/265.full SO - J Pharmacol Exp Ther2014 Aug 01; 350 AB - Pomalidomide, a potent novel immunomodulatory agent, has been developed as a racemic mixture of its R- and S-isomers. Pharmacokinetic (PK) analyses were conducted to determine the PK disposition of the isomers from their PK profiles in humans and monkeys. Modeling and simulation were performed to describe the observed PK profiles and explore potential differences in isomer disposition and exposure. PK profiles of S- and R-isomers were measured in a human absorption, distribution, metabolism, and excretion study after oral administration of racemate. PK profiles of S- and R-isomers were measured in monkeys after intravenous and oral administration of S- or R-isomers and pomalidomide racemate. Modeling and simulation were performed using NONMEM 7.2 (Globomax, Ellicott City, MD) to describe the observed PK profiles of S- and R-isomers in humans and monkeys. The results showed that in humans, the in vivo elimination rate of pomalidomide isomers was lower than the R-/S-interconversion rate, resulting in no clinically relevant difference in overall exposure to the two isomers. However, in monkeys, the in vivo elimination rate was higher than the R-/S-interconversion rate, resulting in 1.72- and 1.55-fold differences in R- versus S-isomer exposures. Monte Carlo simulation indicated that exposure to R- and S-enantiomers in humans should be comparable even if single isomers are administered. Thus, in humans, rapid isomeric interconversion of pomalidomide isomers results in comparable exposure to R- and S-enantiomers regardless of whether pomalidomide is administered as a single enantiomer or as a racemate, therefore justifying the clinical development of pomalidomide as a racemate.