P-Glycoprotein and Breast Cancer Resistance Protein Transporter Inhibition by Cyclosporine and Quinidine on the Pharmacokinetics of Oral Rimegepant in Healthy Subjects.
P-Glycoprotein and Breast Cancer Resistance Protein Transporter Inhibition by Cyclosporine and Quinidine on the Pharmacokinetics of Oral Rimegepant in Healthy Subjects.
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环孢菌素和奎尼丁对健康受试者口服利美克潘药代动力学的P-糖蛋白和乳腺癌耐药蛋白转运蛋白抑制作用。
DOI：
10.1002/cpdd.1088
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发表时间：
2022-07
影响因子：
2
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中科院分区：
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Rimegepant （Nurtec ODT）是一种口服小分子降钙素基因相关肽受体拮抗剂，用于偏头痛的急性和预防性治疗，是体外P糖蛋白和乳腺癌耐药蛋白转运体的底物。我们评估了在健康受试者中同时使用这些转运蛋白的强抑制剂对瑞美佳坦药代动力学的影响。这项单中心、开放标签、随机研究分为两部分，均为两期、两序列、交叉研究。第一部分（n = 15）评估单次口服200mg环孢素（P糖蛋白和乳腺癌耐药蛋白转运蛋白的强抑制剂）对rimegegpant 75mg药代动力学的影响。第2部分（n = 12）评估了单次口服600 mg奎尼丁（一种强选择性P糖蛋白转运蛋白）对75 mg rimegepant药代动力学的影响。与环孢素共给药相比，从时间0到无穷时间，血浆浓度-时间曲线下的边缘面积和最大观察浓度分别增加1.6（1.49‐1.72）和1.41(1.27‐1.57)，基于几何平均比（90%置信区间[ci]）。与奎尼丁共给药显示，从时间0到无穷远，血浆浓度-时间曲线下的边缘物面积增加，最大观察到的浓度几何平均比（90% ci）分别为1.55（1.40‐1.72）和1.67（1.46‐1.91）。强P糖蛋白抑制剂（环孢素，奎尼丁）增加了危险药物暴露（50%,<2倍）。在第1部分和第2部分中，联合用药耐受性良好且安全。环孢素和奎尼丁共同给药对吡格孕酮暴露的类似影响表明，抑制乳腺癌耐药蛋白抑制可能对吡格孕酮暴露的影响较小。
Rimegepant (Nurtec ODT)—an orally administered, small‐molecule calcitonin gene–related peptide receptor antagonist indicated for the acute and preventive treatment of migraine—is a substrate for both the P‐glycoprotein and breast cancer resistance protein transporters in vitro. We evaluated the effects of concomitant administration of strong inhibitors of these transporters on the pharmacokinetics of rimegepant in healthy subjects. This single‐center, open‐label, randomized study was conducted in 2 parts, both of which were 2‐period, 2‐sequence, crossover studies. Part 1 (n = 15) evaluated the effect of a single oral dose of 200‐mg cyclosporine, a strong inhibitor of the P‐glycoprotein and breast cancer resistance protein transporters, on the pharmacokinetics of rimegepant 75 mg. Part 2 (n = 12) evaluated the effect of a single oral dose of 600‐mg quinidine, a strong selective P‐glycoprotein transporter, on the pharmacokinetics of rimegepant 75 mg. Coadministration with cyclosporine showed an increase in rimegepant area under the plasma concentration–time curve from time 0 to infinity and maximum observed concentration based on geometric mean ratios (90% confidence intervals [CIs]) of 1.6 (1.49‐1.72) and 1.41 (1.27‐1.57), respectively, versus rimegepant alone. Coadministration with quinidine showed an increase in rimegepant area under the plasma concentration–time curve from time 0 to infinity and maximum observed concentration geometric mean ratios (90% CIs) of 1.55 (1.40‐1.72) and 1.67 (1.46‐1.91), respectively, versus rimegepant alone. Strong P‐glycoprotein inhibitors (cyclosporine, quinidine) increased rimegepant exposures (>50%, <2‐fold). In parts 1 and 2, rimegepant coadministration was well tolerated and safe. The similar effect of cyclosporine and quinidine coadministration on rimegepant exposure suggests that inhibition of breast cancer resistance protein inhibition may have less influence on rimegepant exposure.