Bhardwaj Rajinder, Morris Beth, Matschke Kyle T, Bertz Richard, Croop Robert, Liu Jing
Certara USA, Princeton, New Jersey, USA.
Biohaven Pharmaceuticals, Inc, New Haven, Connecticut, USA.
Headache. 2025 Feb;65(2):291-302. doi: 10.1111/head.14836. Epub 2024 Oct 4.
Reported here are the results of four rimegepant phase I studies, in healthy participants, aimed at determining the in vivo potential of rimegepant (75 mg) for cytochrome P450 (CYP) 3A4-related drug-drug interactions (DDIs).
Rimegepant orally disintegrating tablet (Pfizer Inc., New York, NY, USA) is a calcitonin gene-related peptide receptor antagonist approved for acute treatment of migraine and preventive treatment of episodic migraine. People with migraine commonly use multiple drug treatments, with the potential for DDIs.
Each study was an open-label, single-arm, single-sequence, crossover study. Rimegepant was tested as a victim drug by separate co-administration of itraconazole (a strong CYP3A4 inhibitor and P-glycoprotein inhibitor) in Study 1, rifampin (a strong CYP3A4 inducer and moderate CYP2C9 inducer) in Study 2, and fluconazole (a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor) in Study 3, and as a perpetrator drug by co-administration with midazolam (a CYP3A4 substrate) in Study 4.
Mean values of single-dose rimegepant maximum concentration (C) and area under the curve from time 0 to infinity (AUC) increased with itraconazole co-administration (n = 22) by 1.42-fold (90% confidence interval [CI] 1.25-1.61) and by 4.14-fold (90% CI 3.87-4.44), respectively, and decreased with rifampin co-administration (n = 21) to 36% (90% CI 31.2-41.4%) and to 19% (90% CI 16.3-21.4%), respectively. Co-administration with fluconazole (n = 23) increased rimegepant mean AUC by 1.80-fold (90% CI 1.68-1.93), with no impact on C (1.04-fold; 90% CI 0.94-1.15). Co-administration of rimegepant single dose (300 mg; n = 14) or multiple doses (150 mg/day; n = 14) increased the mean C of midazolam by 1.38-fold (90% CI 1.13-1.67) and 1.53-fold (90% CI 1.32-1.78), respectively, and the AUC of midazolam by 1.86-fold (90% CI 1.58-2.19) and 1.91-fold (90% CI 1.63-2.25), respectively.
Based on the magnitude of DDIs, these studies indicate the following: co-administration of rimegepant with a strong CYP3A4 inhibitor should be avoided; during co-administration with a moderate CYP3A4 inhibitor, another dose of rimegepant within 48 h should be avoided; co-administration of rimegepant with a strong or moderate CYP3A4 inducer should be avoided; CYP2C9 does not play a meaningful role in rimegepant metabolism; and there is no clinically meaningful CYP3A4 inhibition by rimegepant.
本文报告了四项rimegepant在健康受试者中的I期研究结果，旨在确定rimegepant（75毫克）与细胞色素P450（CYP）3A4相关的药物相互作用（DDIs）的体内可能性。
rimegepant口腔崩解片（辉瑞公司，纽约，美国）是一种降钙素基因相关肽受体拮抗剂，已被批准用于偏头痛的急性治疗和发作性偏头痛的预防性治疗。偏头痛患者通常使用多种药物治疗，存在药物相互作用的可能性。
每项研究均为开放标签、单臂、单序列、交叉研究。在研究1中，通过单独联合使用伊曲康唑（一种强效CYP3A4抑制剂和P-糖蛋白抑制剂）将rimegepant作为受试药物进行测试；在研究2中，使用利福平（一种强效CYP3A4诱导剂和中度CYP2C9诱导剂）；在研究3中，使用氟康唑（一种强效CYP2C9抑制剂和中度CYP3A4抑制剂）；在研究4中，通过与咪达唑仑（一种CYP3A4底物）联合使用将rimegepant作为肇事药物进行测试。
单剂量rimegepant的最大浓度（C）和从时间0到无穷大的曲线下面积（AUC）的平均值，与伊曲康唑联合使用时（n = 22）分别增加了1.42倍（90%置信区间[CI] 1.25 - 1.61）和4.14倍（90% CI 3.87 - 4.44），与利福平联合使用时（n = 21）分别降至36%（90% CI 31.2 - 41.4%）和19%（90% CI 16.3 - 21.4%）。与氟康唑联合使用时（n = 23），rimegepant的平均AUC增加了1.80倍（90% CI 1.68 - 1.93），对C无影响（1.04倍；90% CI 0.94 - 1.15）。rimegepant单剂量（300毫克；n = 14）或多剂量（150毫克/天；n = 14）联合使用时，咪达唑仑的平均C分别增加了1.38倍（90% CI 1.13 - 1.67）和1.53倍（90% CI 1.32 - 1.78），咪达唑仑的AUC分别增加了1.86倍（90% CI 1.58 - 2.19）和1.91倍（90% CI 1.63 - 2.25）。
基于药物相互作用的程度，这些研究表明：应避免rimegepant与强效CYP3A4抑制剂联合使用；在与中度CYP3A4抑制剂联合使用期间，应避免在48小时内再次服用rimegepant；应避免rimegepant与强效或中度CYP3A4诱导剂联合使用；CYP2C9在rimegepant代谢中不起重要作用；并且rimegepant不存在具有临床意义的CYP3A4抑制作用。
