@article {Harbesonjpet.117.241497, author = {Scott L. Harbeson and Adam J. Morgan and Julie F. Liu and Ara M. Aslanian and Sophia Nguyen and Gary W. Bridson and Christopher L. Brummel and Lijun Wu and Roger D. Tung and Lana Pilja and Virginia Braman and Vinita Uttamsingh}, title = {Altering Metabolic Profiles of Drugs by Precision Deuteration 2: Discovery of a Deuterated Analog of Ivacaftor With Differentiated Pharmacokinetics for Clinical Development}, elocation-id = {jpet.117.241497}, year = {2017}, doi = {10.1124/jpet.117.241497}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Ivacaftor is currently used for the treatment of cystic fibrosis as both monotherapy (Kalydeco{\textregistered}) and combination therapy with lumacaftor (Orkambi{\textregistered}). Each therapy targets specific patient populations: Kalydeco treats patients carrying one of nine gating mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR), while Orkambi treats patients homozygous for the F508del CFTR mutation. In this study, we explored the pharmacological and metabolic effects of precision deuteration chemistry on ivacaftor by synthesizing two novel deuterated ivacaftor analogs, CTP-656 (d9-ivacaftor) and d18-ivacaftor. Ivacaftor is administered twice daily and is extensively converted in humans to major metabolites M1 and M6; therefore, the corresponding deuterated metabolites were also prepared. Both CTP-656 and d18-ivacaftor showed similar in vitro pharmacologic potency to ivacaftor, and the deuterated M1 and M6 metabolites showed equivalent pharmacology to the corresponding metabolites of ivacaftor, consistent with previous studies of deuterated compounds. However, CTP-656 exhibited markedly enhanced stability when tested in vitro. The deuterium isotope effects for CTP-656 metabolism (DV = 3.8, DV/K = 2.2) were notably large for a CYP-mediated oxidation. The pharmacokinetic (PK) profile of CTP-656 and d18-ivacaftor were assessed in six healthy volunteers in a single-dose crossover study, which provided the basis for advancing CTP-656 in development. The overall PK profile, including the 15.9 hour t1/2 for CTP-656 suggests that CTP-656 may be dosed once daily thereby enhancing patient adherence. Together, these data continue to validate deuterium substitution as a viable approach for creating novel therapeutic agents with potentially differentiated properties to existing drugs.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2017/06/13/jpet.117.241497}, eprint = {https://jpet.aspetjournals.org/content/early/2017/06/13/jpet.117.241497.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }