Moore Katy H P, Leese Philip T, McNeal Scott, Gray Peter, O'Quinn Stephen, Bye Carole, Sale Mark
Clinical Pharmacology and Experimental Medicine, GlaxoSmithKline, Research Triangle Park, North Carolina 27709-3398, USA.
Clin Ther. 2002 Apr;24(4):583-94. doi: 10.1016/s0149-2918(02)85134-7.
Macrolide antibiotics such as clarithromycin are potent inhibitors of the cytochrome P450 (CYP)3A4 isozyme and have the potential to attenuate the metabolism and increase blood concentrations of drugs metabolized by this pathway. In vitro studies have suggested that sumatriptan is metabolized primarily by the monoamine oxidase-A isozyme and not by CYP3A4.
This study sought to determine the effect of coadministration of clarithromycin dosed to steady state on the pharmacokinetics of a single dose of sumatriptan. A secondary objective was to assess the safety and tolerability of combining these agents.
This was an open-label, randomized, 2-way crossover study in healthy volunteers. During treatment period 1, subjects received either a single oral dose of sumatriptan 50 mg (sumatriptan alone) or clarithromycin 500 mg orally every 12 hours on days 1 to 3 and a single oral dose of sumatriptan 50 mg plus a single oral dose of clarithromycin 500 mg on the morning of day 4 (combination treatment). During treatment period 2, they received the alternative regimen. Equivalence between sumatriptan alone and combination treatment was concluded if the 90% CI for the ratio of reference to test means of loge-transformed data for area under the plasma concentration-time curve extrapolated to infinity (AUC(infinity)) and maximum plasma concentration (Cmax) fell within the interval from 0.8 to 1.25.
In the 24 evaluable subjects (12 men, 12 women) included in the pharmacokinetic analysis, mean sumatriptan AUC(infinity) and Cmax values after administration of combination treatment were 9% and 14% higher, respectively, than the corresponding values after administration of sumatriptan alone. The 90% CI for the ratio of reference to test means for AUC(infinity) was 1.03 to 1.15. The 90% CI for the ratio of reference to test means for Cmax was 1.03 to 1.26, above the traditional bioequivalence criterion. All other pharmacokinetic parameters tested, including nonparametric analysis of the time to Cmax, met the criterion for equivalence between treatments. Both treatments were well tolerated in the 27 subjects (13 men, 14 women) included in the safety analysis.
The extent of absorption of sumatriptan was similar after oral administration alone and in combination with clarithromycin dosed to steady state. These data are consistent with previous reports that sumatriptan is unaffected by coadministration with the potent CYP3A4 inhibitor clarithromycin, supporting concomitant administration of these agents without the need for dose adjustment of sumatriptan in the acute treatment of migraine.
克拉霉素等大环内酯类抗生素是细胞色素P450（CYP）3A4同工酶的强效抑制剂，有可能减弱经此途径代谢的药物的代谢并提高其血药浓度。体外研究表明，舒马曲坦主要由单胺氧化酶-A同工酶代谢，而非由CYP3A4代谢。
本研究旨在确定给予稳态剂量的克拉霉素与单剂量舒马曲坦合用时对其药代动力学的影响。次要目的是评估联合使用这些药物的安全性和耐受性。
这是一项在健康志愿者中进行的开放标签、随机、双向交叉研究。在治疗期1，受试者在第1至3天接受单次口服50 mg舒马曲坦（单独使用舒马曲坦）或每12小时口服500 mg克拉霉素，并在第4天上午接受单次口服50 mg舒马曲坦加单次口服500 mg克拉霉素（联合治疗）。在治疗期2，他们接受替代方案。如果血浆浓度-时间曲线下面积外推至无穷大（AUC（无穷大））和最大血浆浓度（Cmax）的对数转换数据的参比均值与受试均值之比的90%置信区间落在0.8至1.25范围内，则判定单独使用舒马曲坦与联合治疗等效。
在药代动力学分析纳入的24名可评估受试者（12名男性，12名女性）中，联合治疗给药后舒马曲坦的平均AUC（无穷大）和Cmax值分别比单独使用舒马曲坦给药后的相应值高9%和14%。AUC（无穷大）的参比均值与受试均值之比的90%置信区间为1.03至1.15。Cmax的参比均值与受试均值之比的90%置信区间为1.03至1.26，高于传统生物等效性标准。所测试的所有其他药代动力学参数，包括Cmax达峰时间的非参数分析，均符合治疗间等效性标准。在安全性分析纳入的27名受试者（13名男性，14名女性）中，两种治疗的耐受性均良好。
单独口服舒马曲坦以及与稳态剂量的克拉霉素联合口服后，舒马曲坦的吸收程度相似。这些数据与之前的报道一致，即舒马曲坦不受与强效CYP3A4抑制剂克拉霉素合用的影响，支持在偏头痛急性治疗中联合使用这些药物，而无需调整舒马曲坦的剂量。
