RT Journal Article
SR Electronic
T1 Modeling and Simulation to Probe the Pharmacokinetic Disposition of Pomalidomide <em>R</em>- and <em>S</em>-Enantiomers
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 265
OP 272
DO 10.1124/jpet.114.215251
VO 350
IS 2
A1 Yan Li
A1 Simon Zhou
A1 Matthew Hoffmann
A1 Gondi Kumar
A1 Maria Palmisano
YR 2014
UL http://jpet.aspetjournals.org/content/350/2/265.abstract
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.