Effect of CYP3A Inhibition and Induction on the Pharmacokinetics of Suvorexant: Two Phase I, Open-Label, Fixed-Sequence Trials in Healthy Subjects.
Publication/Presentation Date
5-1-2019
Abstract
BACKGROUND AND OBJECTIVES: Suvorexant is an orexin receptor antagonist indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. As suvorexant is metabolized primarily by Cytochrome P450 3A (CYP3A), and its pharmacokinetics may be affected by CYP3A modulators, the effects of CYP3A inhibitors (ketoconazole or diltiazem) or an inducer (rifampin [rifampicin]) on the pharmacokinetics, safety, and tolerability of suvorexant were investigated.
METHODS: In two Phase I, open-label, fixed-sequence trials (Studies P008 and P038), healthy subjects received a single oral dose of suvorexant followed by co-administration with multiple once-daily doses of strong/moderate CYP3A inhibitors (ketoconazole/diltiazem) or a strong CYP3A inducer (rifampin). Treatments were administered in the morning: suvorexant 4 mg with ketoconazole 400 mg (Study P008; N = 10), suvorexant 20 mg with diltiazem 240 mg (Study P038; N = 20), and suvorexant 40 mg with rifampin 600 mg (Study P038; N = 10). Area under the plasma concentration-time curve from time zero to infinity (AUC
RESULTS: Co-administration with ketoconazole resulted in increased exposure to suvorexant [AUC
CONCLUSIONS: These results are consistent with expectations that strong CYP3A inhibitors and inducers exert marked effects on suvorexant pharmacokinetics. In the context of a limited sample size, single suvorexant doses were generally well tolerated in healthy subjects when co-administered with/without a CYP3A inhibitor/inducer.
Volume
39
Issue
5
First Page
441
Last Page
451
ISSN
1179-1918
Published In/Presented At
Wrishko, R. E., McCrea, J. B., Yee, K. L., Liu, W., Panebianco, D., Mangin, E., Chakravarthy, M., Martinez-Cantarin, M. P., & Kraft, W. K. (2019). Effect of CYP3A Inhibition and Induction on the Pharmacokinetics of Suvorexant: Two Phase I, Open-Label, Fixed-Sequence Trials in Healthy Subjects. Clinical drug investigation, 39(5), 441–451. https://doi.org/10.1007/s40261-019-00764-x
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
30810914
Department(s)
Administration and Leadership
Document Type
Article