Double-blind crossover study to assess potential differences in cytochrome P450 3A4 activity in healthy subjects...

Because glucocorticoids and the neurokinin-1 receptor antagonist aprepitant influence CYP3A4 activity, this study assessed whether aprepitant added to a 5-HT(3) antagonist and glucocorticoid would affect CYP3A4 induction.

In this double-blind, 2-period crossover study, 12 subjects were randomized to receive a triple regimen (oral aprepitant [A] 125 mg, intravenous ondansetron [O] 32 mg, and oral dexamethasone [D] 12 mg day 1; A 80 mg and D 8 mg days 2-3; D 8 mg day 4) in 1 of 2 periods, and a dual regimen (O 32 mg and D 20 mg day 1; D 8 mg bid days 2-4); the D dose was adjusted to account for known dexamethasone/aprepitant interaction. Oral (2 mg) and intravenous (1 mg) stable isotope ((13)C(5) (15)N(1))-labeled midazolam were simultaneously given as probes on days -1, 6, 8, 15, and 22 of each period. If the a priori 90% confidence interval for the day 6 geometric mean oral midazolam AUC(0-∞) ratio (triple/dual regimen) of fold-change from baseline was above 0.5, it would be concluded that there was no clinically meaningful between-regimen difference in CYP3A4 activity.

Day 6 oral midazolam AUC(0-∞) geometric mean fold-change from baseline was 0.84 (0.30-1.58 with A, 0.46-1.69 without A). The ratio of geometric mean oral midazolam AUC(0-∞) fold-changes was 1.00 (90% confidence interval 0.80, 1.25).

Aprepitant plus a 5-HT(3) antagonist and dexamethasone is unlikely to have a significant additional inductive effect on CYP3A4 activity beyond that of the dual regimen.