Effect of Aprepitant 40 mg on Cyto - chrome P-450 2C9 Activity: A Random- ized, Double-Blind, Placebo-Controlled, Parallel-Group Study in Healthy Young Adults

This study evaluated effects of the neurokinin-1 receptor antagonis aprepitant on CYP2C9 as measured by the pharmacokinetics of oral tolbutamide, a substrate of CYP2C9. Healthy young adults were randomized to receive either oral aprepitant 40mg or placebo. All subjects received oral tolbutamide 500 mg at baseline (Day -7 to -5), and on Days 2, 4, 8, and 15. The primary variable of interest was the aprepitant/placebo ratio of geometric mean fold-change from baseline in tolbutamide AUC 0-∞ on Days 2, 4, 8, and 15. The natural-log-transformed foldchange in AUC was analyzed using a linear mixed-model for repeated measures. Ratios of geometric means for tolbutamide AUC fold-change from baseline on Days 2, 4, 8, and 15 were 0.92, 0.84, 0.85, and 0.90, respectively. Twenty-eight nonserious clinical adverse events were reported. A single 40 mg oral dose of aprepitant, coadministered with tolbutamide 500 mg, has no clinically relevant effect on CYP2C9 activity and is generally well tolerated.