The Hamilton Consulting Group, Boulder, CO, USA.
Cancer Chemother Pharmacol. 2014 Mar;73(3):613-21. doi: 10.1007/s00280-014-2390-3. Epub 2014 Jan 29.
Erlotinib, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine is approved for the treatment for non-small cell lung cancer and pancreatic cancer. Because erlotinib is metabolized predominately by CYP3A4, co-administration of compounds that increase CYP3A4 activity may alter the efficacy and safety of erlotinib therapy. Two phase I studies were conducted in healthy male subjects to evaluate the effect of pre- or co-administered rifampicin, a CYP3A4 inducer, on the pharmacokinetics of erlotinib.
Study 1 included Groups A (erlotinib 150 mg days 1 and 15, rifampicin 600 mg days 8-14) and B (erlotinib 150 mg days 1 and 15) in a parallel group study design. Study 2 subjects received erlotinib 150 mg day 1, erlotinib 450 mg day 15, and rifampicin 600 mg days 8-18. The primary endpoint in each study was the ratio of exposure (AUC0-∞ and C max) between days 1 and 15. Urinary cortisol metabolic induction ratios were determined in Study 1 for Group A subjects only.
In Study 1, the geometric mean ratios of AUC0-∞ and C max were 33 and 71 %, respectively, and the mean cortisol metabolic index increased from 7.4 to 27.0, suggesting cytochrome P450 (CYP) enzyme induction. In Study 2, the geometric mean ratios for AUC0-∞ and C max were 19 and 34 % (when dose adjusted from 450 to 150 mg erlotinib), respectively, a greater relative decrease than observed in Study 1.
Erlotinib exposure (AUC0-∞ and C max) was reduced after pre- or concomitant dosing with rifampicin. Doses of ≥450 mg erlotinib may be necessary to compensate for concomitant medications with strong CYP3A4 enzyme induction effect.
厄洛替尼，N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺，被批准用于治疗非小细胞肺癌和胰腺癌。由于厄洛替尼主要通过 CYP3A4 代谢，联合使用可增加 CYP3A4 活性的化合物可能会改变厄洛替尼治疗的疗效和安全性。两项在健康男性受试者中进行的 I 期研究评估了预先或同时给予利福平（CYP3A4 诱导剂）对厄洛替尼药代动力学的影响。
研究 1 包括在平行组设计的 A 组（厄洛替尼 150mg 第 1 天和第 15 天，利福平 600mg 第 8 天至第 14 天）和 B 组（厄洛替尼 150mg 第 1 天和第 15 天）。研究 2 受试者接受厄洛替尼 150mg 第 1 天，厄洛替尼 450mg 第 15 天，利福平 600mg 第 8 天至第 18 天。每个研究的主要终点是第 1 天和第 15 天之间的暴露（AUC0-∞和 C max）比值。仅在研究 1 中对 A 组受试者测定尿皮质醇代谢诱导比值。
在研究 1 中，AUC0-∞和 C max 的几何均数比值分别为 33%和 71%，皮质醇代谢指数均值从 7.4 增加到 27.0，提示细胞色素 P450（CYP）酶诱导。在研究 2 中，AUC0-∞和 C max 的几何均数比值分别为 19%和 34%（当厄洛替尼剂量从 450mg 调整为 150mg 时），相对于研究 1 观察到的比值下降更大。
在预先或同时给予利福平后，厄洛替尼的暴露（AUC0-∞和 C max）减少。可能需要给予≥450mg 的厄洛替尼剂量来补偿具有强 CYP3A4 酶诱导作用的伴随药物。
