Double-blind crossover study to assess potential differences in cytochrome P450 3A4 activity in healthy subjects receiving ondansetron plus dexamethasone, with and without aprepitant.
Publication/Presentation Date
6-1-2011
Abstract
PURPOSE: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
Volume
67
Issue
6
First Page
1313
Last Page
1321
ISSN
1432-0843
Published In/Presented At
Stoch, S. A., Gargano, C., Valentine, J., Braun, M. P., Murphy, M. G., Fedgchin, M., Majumdar, A., Pequignot, E., Gottesdiener, K. M., Petty, K. J., Panebianco, D., Dean, D., Kraft, W. K., & Greenberg, H. E. (2011). Double-blind crossover study to assess potential differences in cytochrome P450 3A4 activity in healthy subjects receiving ondansetron plus dexamethasone, with and without aprepitant. Cancer chemotherapy and pharmacology, 67(6), 1313–1321. https://doi.org/10.1007/s00280-010-1421-y
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
20734049
Department(s)
Administration and Leadership
Document Type
Article