Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 432, Houston, TX 77030, USA.
Invest New Drugs. 2011 Jun;29(3):499-505. doi: 10.1007/s10637-009-9380-z. Epub 2010 Jan 22.
To assess the pharmacokinetics and evaluate potential drug-drug interactions between erlotinib, paclitaxel and carboplatin.
1,079 previously untreated patients with advanced NSCLC were enrolled and randomized in a phase III trial (TRIBUTE) to receive either erlotinib or placebo in combination with paclitaxel 200 mg/m2 IV over 3 h and carboplatin at a calculated dose to achieve an AUC 6 mg∙min/mL. To determine possible drug-drug interaction with this combination, a subset of 24 (12 erlotinib, 12 placebo) patients were enrolled onto an intensive pharmacokinetic (IPK) substudy group at a single site. All IPK patients received either erlotinib 150 mg/day or placebo-controlled tablets. Analyses were completed using validated analytical methodologies. Non-compartmental modeling was utilized to estimate PK parameters.
Complete blood sampling for pharmacokinetic analysis was obtained in 21 of 24 patients. Mean AUC(0-τ) for erlotinib and the OSI-420 metabolite were 29,997 ng∙h/mL and 3,020 ng∙h/mL, respectively. Mean (SD) paclitaxel clearances (L/h/M(2)) were 11.7 (3.4) and 12.7 (6.7) in the placebo and erlotinib treatment groups, respectively. The resultant paclitaxel AUC(0-∞) (ng∙h/mL) was 18,400 (5,300) for the placebo group and 17,800 (5,500) for the erlotinib group. For carboplatin, the mean (SD) clearances (L/h) were 16.8 (3.9) and 16.1 (4.4) for the placebo and erlotinib groups, respectively. The resultant carboplatin AUC(0-∞) (ng/mL∙h) were 49,900 (9,700) for the placebo group and 48,400 (11,900) for the erlotinib group. No significant differences were observed in these paclitaxel or carboplatin pharmacokinetic group comparisons.
The addition of erlotinib to a standard chemotherapy regimen for NSCLC did not alter the systemic exposures (AUC(0-∞)) of paclitaxel (p = 0.80) and carboplatin (p = 0.756) when erlotinib-treated patients were compared to placebo-treated patients. The pharmacokinetics of erlotinib and its metabolite OSI-420 did not appear to be altered by the concomitant administration of paclitaxel and carboplatin.
评估厄洛替尼、紫杉醇和卡铂之间的药代动力学和潜在的药物相互作用。
1079 例未经治疗的晚期 NSCLC 患者被纳入一项 III 期试验（TRIBUTE），随机接受厄洛替尼或安慰剂联合紫杉醇 200 mg/m2 静脉滴注 3 小时和卡铂，计算剂量以达到 AUC 6 mg·min/mL。为了确定与该联合用药的潜在药物相互作用，在一个单一地点纳入了 24 名（12 名厄洛替尼，12 名安慰剂）患者的亚组进行密集药代动力学（IPK）亚研究组。所有 IPK 患者均接受厄洛替尼 150 mg/天或安慰剂对照片剂治疗。使用经过验证的分析方法完成分析。非房室模型用于估计 PK 参数。
24 名患者中的 21 名完成了用于药代动力学分析的全血采样。厄洛替尼和 OSI-420 代谢物的 AUC(0-τ) 分别为 29997ng·h/mL 和 3020ng·h/mL。安慰剂和厄洛替尼治疗组的紫杉醇清除率（L/h/M2）分别为 11.7（3.4）和 12.7（6.7）。安慰剂组的紫杉醇 AUC(0-∞)（ng·h/mL）为 18400（5300），厄洛替尼组为 17800（5500）。对于卡铂，安慰剂组和厄洛替尼组的平均（SD）清除率（L/h）分别为 16.8（3.9）和 16.1（4.4）。安慰剂组的卡铂 AUC(0-∞)（ng/mL·h）为 49900（9700），厄洛替尼组为 48400（11900）。这些紫杉醇或卡铂药代动力学组比较中未观察到显著差异。
与安慰剂组相比，厄洛替尼组的患者接受厄洛替尼联合标准化疗方案治疗 NSCLC 时，并未改变紫杉醇（p=0.80）和卡铂（p=0.756）的全身暴露（AUC(0-∞)）。同时给予厄洛替尼和卡铂似乎不会改变厄洛替尼及其代谢物 OSI-420 的药代动力学。
