Abstract 3357: CTP-221, a deuterated S-enantiomer of lenalidomide, is greatly stabilized to epimerization and results in a more desirable pharmacokinetic profile than racemic lenalidomide.
Authors: Uttamsingh Vinita , Gallegos Richard , Cheng Changfu , Aslanian Ara , Liu Julie Fields , Tung Roger , Wu Lijun 
Published: August 2014

Abstract
IMiD-class compounds, including thalidomide, lenalidomide, and pomalidomide, have been developed as racemic mixtures of S- and R-enantiomers. The isolated enantiomers of thalidomide are known to have distinct biological activities. For example, the well-documented sedative effects of thalidomide are correlated with the R-enantiomer (Eriksson et al., 2000), whereas S-thalidomide exhibits enhanced potency for TNF-α inhibition compared to the R-enantiomer (Wnendt et al., 1996; Moreira et al., 1993). We have demonstrated that S-lenalidomide is more potent than racemic or R-lenalidomide in biological activities that are believed to be important for clinical efficacy of lenalidomide. Due to facile in vivo conversion, isolated S-enantiomers of IMiDs have not been developed clinically. Lenalidomide (Revlimid®) is a racemic mixture of S- and R-enantiomers that interconvert through epimerization. Revlimid is labeled for the treatment of 5q-myelodysplastic syndromes (MDS) and multiple myeloma.
CTP-221 is a deuterium-modified analog of S-lenalidomide containing deuterium atoms at key positions including lenalidomide's chiral center. Deuterium modification has the potential, albeit unpredictably, to alter the metabolic fate and hence the pharmacokinetic disposition of drugs, especially those that are biotransformed via the cleavage of carbon-hydrogen bonds (Fisher et al, 2006). The effect of deuterium modification on the epimerization rate and pharmacokinetic profile of CTP-221 was investigated in vitro and in vivo in mice, rats and monkeys.
The rates of epimerization of CTP-221 and S-lenalidomide were compared in vitro in whole blood from mouse, rat, monkey, and human. It was found that CTP-221 was 2- to 3-fold more stable to epimerization than S-lenalidomide in the four species. To compare the in vivo pharmacokinetic profiles of CTP-221 and racemic lenalidomide, the compounds (10 mg/kg, PO) were administered to mice, rats and monkeys. In all three species, the exposure (AUC) of S- and R-lenalidomide following administration of racemic lenalidomide was about 50-57% and 43-50%, respectively, of the sum of the AUC of the individual enantiomers. However, when CTP-221 was administered, the AUC of CTP-221 and the deuterated R-enantiomers formed in vivo were about 96-99% and 1-4% respectively, of the sum of the AUC of the two enantiomers. Thus, CTP-221 epimerizes to a minimal extent in vivo and its administration provides exposure to very low levels of the R-enantiomer.
In conclusion, the stabilization of CTP-221 via deuterium substitution resulted in maximal exposure to the more potent S-enantiomer and minimal exposure to the R-enantiomer. As a result, CTP-221 has the potential for improved potency and therapeutic index in comparison to racemic lenalidomide.
Citation Format: Vinita Uttamsingh, Richard Gallegos, Changfu Cheng, Ara Aslanian, Julie Fields Liu, Roger Tung, Lijun Wu. CTP-221, a deuterated S-enantiomer of lenalidomide, is greatly stabilized to epimerization and results in a more desirable pharmacokinetic profile than racemic lenalidomide. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3357. doi:10.1158/1538-7445.AM2013-3357