Wind Sven, Giessmann Thomas, Jungnik Arvid, Brand Tobias, Marzin Kristell, Bertulis Julia, Hocke Julia, Gansser Dietmar, Stopfer Peter
Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany,
Clin Drug Investig. 2014 Mar;34(3):173-82. doi: 10.1007/s40261-013-0161-2.
Afatinib is a potent, irreversible, ErbB family blocker in clinical development for the treatment of advanced non-small cell lung cancer, metastatic head and neck cancer, and other solid tumours. As afatinib is a substrate for the P-glycoprotein (P-gp) pump transporter the three studies presented here investigated the pharmacokinetics of afatinib in the presence of a potent inhibitor (ritonavir) or inducer [rifampicin (rifampin)] of P-gp.
We conducted phase I, open-label, single-centre studies in healthy male volunteers who received a single once-daily oral dose of afatinib (20 or 40 mg) together with either ritonavir or rifampicin; two studies had a randomised, two- and three-way crossover design and the third was a non-randomised, two-period sequential study.
When afatinib 20 mg was administered 1 h after ritonavir, afatinib geometric mean (gMean) maximum plasma concentration (C max) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) increased by 38.5 and 47.6 %, respectively. Coadministration of ritonavir either simultaneously or 6 h later than afatinib 40 mg resulted in minimal increase in the afatinib gMean C max and AUC∞ (4.1 and 18.6 % for simultaneous administration with AUC∞ not completely within the bioequivalence limits; 5.1 and 10.8 % for timed administration within the bioequivalence limits). Administration of afatinib 40 mg in the presence of rifampicin led to reduction in C max and AUC∞ by 21.6 and 33.8 %, respectively. In all studies, P-gp modulation mainly affected the extent of absorption of afatinib; there was no change in the terminal elimination half-life. The overall safety profile of afatinib was acceptable.
Coadministration of potent P-gp modulators had no clinically relevant effect on afatinib exposure. Effects of potent P-gp inhibitors were minimal at higher afatinib doses and can be readily managed by the timing of concomitant therapy. As afatinib is not a relevant modulator or substrate of cytochrome P450 enzymes, the drug-drug interaction potential is considered to be low.
阿法替尼是一种强效、不可逆的表皮生长因子受体（ErbB）家族阻滞剂，正处于临床开发阶段，用于治疗晚期非小细胞肺癌、转移性头颈癌及其他实体瘤。由于阿法替尼是P-糖蛋白（P-gp）泵转运体的底物，因此本文所呈现的三项研究考察了在强效P-gp抑制剂（利托那韦）或诱导剂[利福平]存在的情况下阿法替尼的药代动力学。
我们在健康男性志愿者中开展了I期开放标签单中心研究，这些志愿者每日单次口服阿法替尼（20或40mg），同时服用利托那韦或利福平；两项研究采用随机、两交叉和三交叉设计，第三项研究为非随机、两阶段序贯研究。
当在利托那韦给药1小时后给予20mg阿法替尼时，阿法替尼的几何平均最大血浆浓度（Cmax）和从零至无穷大的血浆浓度-时间曲线下面积（AUC∞）分别增加了38.5%和47.6%。利托那韦与40mg阿法替尼同时给药或在其6小时后给药，导致阿法替尼的几何平均Cmax和AUC∞增加极少（同时给药时分别为4.1%和18.6%，AUC∞不完全在生物等效性范围内；定时给药时分别为5.1%和10.8%，在生物等效性范围内）。在利福平存在的情况下给予40mg阿法替尼导致Cmax和AUC∞分别降低21.6%和33.8%。在所有研究中，P-gp调节主要影响阿法替尼的吸收程度；终末消除半衰期无变化。阿法替尼的总体安全性良好。
强效P-gp调节剂与阿法替尼合用对阿法替尼的暴露量无临床相关影响。在较高阿法替尼剂量下，强效P-gp抑制剂的影响极小，可通过调整联合治疗的给药时间轻松处理。由于阿法替尼不是细胞色素P450酶的相关调节剂或底物，因此其药物相互作用潜力被认为较低。
