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Effect of cenobamate on the single-dose pharmacokinetics of multiple cytochrome P450 probes using a cocktail approach in healthy subjects.
- Source :
-
Clinical and translational science [Clin Transl Sci] 2022 Apr; Vol. 15 (4), pp. 899-911. Date of Electronic Publication: 2021 Dec 13. - Publication Year :
- 2022
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Abstract
- This study was designed to evaluate the effects of cenobamate, an antiseizure medication for focal seizures, on the pharmacokinetics of cytochrome P450 probes (bupropion, CYP2B6; midazolam, CYP3A4/5; warfarin, CYP2C9; and omeprazole, CYP2C19) in healthy subjects. Probes were administered alone on days 1 (bupropion) and 7 (midazolam/warfarin/omeprazole), and with cenobamate 100 mg/day on day 69 (midazolam) and cenobamate 200 mg/day on days 99 (bupropion) and 105 (midazolam/warfarin/omeprazole). No significant interaction was concluded if 90% confidence intervals (CIs) for geometric mean ratios (GMRs) for area under the curve (AUC) and maximum concentration of CYP substrates and/or their metabolites were within the no-effect interval (0.80-1.25). When co-administered with cenobamate 100 mg/day, AUC from time of administration up to the time of the last quantifiable concentration (AUC <subscript>0-last</subscript> ) GMR (90% CIs) for midazolam was 0.734 (0.647-0.832). When co-administered with cenobamate 200 mg/day, AUC <subscript>0-last</subscript> GMRs (90% CI) for midazolam, bupropion, S-warfarin, and omeprazole were 0.277 (0.238-0.323), 0.615 (0.522-0.724), 1.14 (1.10-1.18), and 2.07 (1.44-2.98), respectively. Co-administration of cenobamate with midazolam and bupropion probes led to values that were outside and below the no effect boundary, indicating that cenobamate induces the CYP3A4/5 and CYP2B6 enzymes. Co-administration of cenobamate led to omeprazole values which were outside and above the no-effect boundary, but with high variability, suggesting that cenobamate may moderately inhibit CYP2C19 activity. No effect on CYP2C9 was observed with the cenobamate and warfarin combination. Co-administration of cenobamate with these probes drugs was well-tolerated. In this study, 200 mg/day cenobamate moderately induced CYP3A4/5 (dose-dependently; 100 mg/day was a weak inducer), was a weak inducer of CYP2B6, moderately inhibited CYP2C19, and had a negligible effect on CYP2C9.<br /> (© 2021 SK Life Science, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- Bupropion pharmacokinetics
Carbamates
Chlorophenols
Cytochrome P-450 CYP2B6 metabolism
Cytochrome P-450 CYP2C19 genetics
Cytochrome P-450 CYP2C9
Cytochrome P-450 Enzyme System metabolism
Drug Interactions
Healthy Volunteers
Humans
Omeprazole pharmacokinetics
Pharmaceutical Preparations
Tetrazoles
Warfarin pharmacokinetics
Cytochrome P-450 CYP3A metabolism
Midazolam pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1752-8062
- Volume :
- 15
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Clinical and translational science
- Publication Type :
- Academic Journal
- Accession number :
- 34877801
- Full Text :
- https://doi.org/10.1111/cts.13204