Modeling and Simulation to Probe the Pharmacokinetic Disposition of PomalidomideR- andS-Enantiomers

Abstract

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 Sand 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 Risomers 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-/Sinterconversion 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.

Chiral Separation of Uncharged Pomalidomide Enantiomers Using Carboxymethyl‐β‐Cyclodextrin: A Validated Capillary Electrophoretic Method

“…It has also recently been shown that S ‐enantiomers of thalidomide and its analogs bind preferentially to cereblon, the newly identified primarily protein target of IMiDs, further emphasizing the distinctive biological properties of the configurational isomers . Even though the different pharmacological effects of the enantiomers are already known, IMiDs are still developed and marketed as racemates, obviously to the fast racemization of the chiral center . In the case of POM (Fig.…”

“…8,9 Even though the different pharmacological effects of the enantiomers are already known, IMiDs are still developed and marketed as racemates, obviously to the fast racemization of the chiral center. [10][11][12][13] In the case of POM ( Fig. 1), its (À)-S-enantiomer was even advanced into clinical trials.…”

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

“…Although there is limited data available and the enantiomers interconvert during the time course of the studies, a few groups have shown that the teratogenicity, in vitro antiinflammatory activity, and in vivo efficacy of protonated thalidomide analogs are caused, in large part, by the (S)-enantiomer (22,(36)(37)(38). (S)-pomalidomide was originally advanced into clinical trials as ENMD 0995 (39) but soon abandoned because of the rapid racemization of the exchangeable chiral center (28,29). Finally, it has recently been shown by X-ray crystallography that the (S)-enantiomers of thalidomide, lenalidomide, and pomalidomide preferentially bind a newly identified target, cereblon (CRBN), believed to be responsible for their efficacy and teratogenicity in a cocrystal with the DDB1-CRBN complex, where DDB1 stands for DNA damage-binding protein 1 (40).…”

LC–MS/MS and chiroptical spectroscopic analyses of multidimensional metabolic systems of chiral thalidomide and its derivatives

“…23,24 Recently, cereblon (CRBN) has been identified as a TD target protein for suppressing the production of growth factor FGF8 during the organogenesis stage and inducing malformation or total absence of a fetal limb. 22,[30][31][32][33][34][35][36][37] However, it is uncertain whether the existence of various structures including TD, its derivatives, and their metabolites is the Different combinations of substituents R i (i = 1, 2, 3, 4, 5) on TD determines different derivatives and structural isomers of mono-hydroxylated metabolites. 28,29 The medicinal properties of TD such as its hypnotic, sedative, and teratogenic effects seem to result from these multiple effects, which are still indeterminate.…”