Ivacaftor is currently used for the treatment of cystic fibrosis as both 
monotherapy (Kalydeco; Vertex Pharmaceuticals, Boston, MA) and combination 
therapy with lumacaftor (Orkambi; Vertex Pharmaceuticals). Each therapy targets 
specific patient populations: Kalydeco treats patients carrying one of nine 
gating mutations in the cystic fibrosis transmembrane conductance regulator 
(CFTR) protein, whereas 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 in vitro pharmacologic 
potency similar to that in ivacaftor, and the deuterated M1 and M6 metabolites 
showed pharmacology equivalent to that in the corresponding metabolites of 
ivacaftor, which is consistent with the findings of 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 cytochrome P450-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 half-life 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 properties potentially differentiated from existing 
drugs.