LeBel M, Masson E, Guilbert E, Colborn D, Paquet F, Allard S, Vallée F, Narang P K
Anapharm, Inc., Ste-Foy, Québec, Canada.
J Clin Pharmacol. 1998 Nov;38(11):1042-50. doi: 10.1177/009127009803801109.
This open-label, randomized, three-way crossover study of 28 healthy premenopausal women was conducted to compare the impact of concomitant rifabutin and rifampicin on the safety, pharmacokinetics, and pharmacodynamics of the oral contraceptives ethinylestradiol and norethindrone (Ortho-Novum 1/35; Ortho Pharmaceutical, Raritan, NJ). Each participant received oral contraceptives daily for 21 days for the first control cycle, then was randomized to one of two sequences to receive oral contraceptives with concomitant rifampicin and rifabutin at equal doses of 300 mg/day for 10 days. Ethinylestradiol, norethindrone, follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, rifampicin, and rifabutin (and metabolite) were measured in plasma over the same time frames in all three cycles. Safety was assessed from before the beginning to the end of each cycle. Twenty-two subjects completed all three cycles. Compared with the control cycle, rifabutin and rifampicin significantly altered the disposition of the oral contraceptive. Area under the concentration-time curve from 0 to 24 hours (AUC0-24) and maximum plasma concentration (Cmax) of ethinylestradiol decreased by 64% and 42%, respectively, after coadministration with rifampicin and by 35% and 20%, respectively, after coadministration with rifabutin. The AUC0-24 of norethindrone decreased by 60% and 20% after coadministration with rifampicin and rifabutin, respectively. Unlike progesterone levels, FSH and LH levels increased during coadministration with rifampicin and rifabutin. The incidence of spotting was significantly higher after coadministration with rifampicin (36.4%) and rifabutin (21.7%) than during the control cycle (3.7%). Although both rifampicin and rifabutin affected the pharmacokinetics of ethinylestradiol and norethindrone, the magnitude of this effect was more pronounced with rifampicin. Likewise, the fact that the highest incidence of spotting occurred with rifampicin was consistent with higher metabolic induction by rifampicin. Despite the fact that there was no change in progesterone levels, it is recommended that patients be advised to use additional contraceptive methods while receiving rifabutin or rifampicin with oral contraceptives to prevent inadvertent pregnancy.
这项开放标签、随机、三交叉研究纳入了28名健康的绝经前女性，旨在比较利福布汀和利福平同时使用时对口服避孕药炔雌醇和炔诺酮（炔诺酮炔雌醇片1/35；美国新泽西州拉里坦市奥索制药公司）安全性、药代动力学和药效学的影响。在第一个对照周期中，每位参与者每天服用口服避孕药21天，然后随机分为两个序列之一，接受口服避孕药并同时服用利福平及利福布汀，剂量均为300mg/天，持续10天。在所有三个周期的相同时间点测定血浆中的炔雌醇、炔诺酮、促卵泡激素（FSH）、促黄体生成素（LH）、孕酮、利福平及利福布汀（及其代谢物）。从每个周期开始前至结束时评估安全性。22名受试者完成了所有三个周期。与对照周期相比，利福布汀和利福平显著改变了口服避孕药的处置。与利福平合用时，炔雌醇0至24小时浓度-时间曲线下面积（AUC0-24）和血浆最大浓度（Cmax）分别下降64%和42%；与利福布汀合用时，分别下降35%和20%。与利福平及利福布汀合用时，炔诺酮的AUC0-24分别下降60%和20%。与孕酮水平不同，与利福平及利福布汀合用时FSH和LH水平升高。与利福平（36.4%）及利福布汀（21.7%）合用时点滴出血的发生率显著高于对照周期（3.7%）。虽然利福布汀和利福平均影响炔雌醇和炔诺酮的药代动力学，但利福平的这种作用更为明显。同样，利福平导致的点滴出血发生率最高这一事实与利福平更高的代谢诱导作用一致。尽管孕酮水平没有变化，但建议告知患者在服用利福布汀或利福平并同时服用口服避孕药时使用额外的避孕方法，以防止意外怀孕。
