SK Life Science, Inc., Paramus, New Jersey, USA.
Clin Transl Sci. 2022 Apr;15(4):899-911. doi: 10.1111/cts.13204. Epub 2021 Dec 13.
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 ) GMR (90% CIs) for midazolam was 0.734 (0.647-0.832). When co-administered with cenobamate 200 mg/day, AUC 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.
本研究旨在评估抗癫痫药物 Cenobamate 对细胞色素 P450 探针（安非他酮，CYP2B6；咪达唑仑，CYP3A4/5；华法林，CYP2C9；和奥美拉唑，CYP2C19）在健康受试者中的药代动力学的影响。探针在第 1 天（安非他酮）和第 7 天（咪达唑仑/华法林/奥美拉唑）单独给药，在第 69 天（咪达唑仑）和第 99 天（安非他酮）和第 105 天（咪达唑仑/华法林/奥美拉唑）与 Cenobamate 100mg/天联合给药。如果 CYP 底物及其代谢物的 AUC 和最大浓度的几何均数比值（GMR）的 90%置信区间（CI）在无效应区间（0.80-1.25）内，则认为没有明显的相互作用。当与 100mg/天的 Cenobamate 联合给药时，咪达唑仑的给药时间至最后可定量浓度的 AUC（AUC）GMR（90%CI）为 0.734（0.647-0.832）。当与 200mg/天的 Cenobamate 联合给药时，咪达唑仑、安非他酮、S-华法林和奥美拉唑的 AUC GMR（90%CI）分别为 0.277（0.238-0.323）、0.615（0.522-0.724）、1.14（1.10-1.18）和 2.07（1.44-2.98）。Cenobamate 与咪达唑仑和安非他酮探针联合给药导致的数值超出且低于无效应边界，表明 Cenobamate 诱导 CYP3A4/5 和 CYP2B6 酶。Cenobamate 与奥美拉唑联合给药导致的数值超出且高于无效应边界，但具有较高的变异性，表明 Cenobamate 可能适度抑制 CYP2C19 活性。Cenobamate 与华法林组合对 CYP2C9 没有影响。与这些探针药物联合使用 Cenobamate 耐受性良好。在这项研究中，200mg/天的 Cenobamate 适度诱导 CYP3A4/5（剂量依赖性；100mg/天是弱诱导剂），是 CYP2B6 的弱诱导剂，适度抑制 CYP2C19，对 CYP2C9 几乎没有影响。
