Clinical pharmacokinetics of erlotinib in patients with solid tumors and. exposure-safety relationship in patients with non-small cell lung cancer
Clinical pharmacokinetics of erlotinib in patients with solid tumors and. exposure-safety relationship in patients with non-small cell lung cancer
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DOI：
10.1016/j.clpt.2006.04.007
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发表时间：
2006-08-01
影响因子：
6.7
通讯作者：
Lum, Bert L.
中科院分区：
文献类型：
--
作者：
Lu, Jian-Feng;Eppler, Steve M.;Lum, Bert L.
目的：我们的目的是评估厄洛替尼在大型实体肿瘤患者群体中的药代动力学，确定协变量，并探讨接受单药厄洛替尼治疗的非小细胞肺癌患者的暴露与安全性结局（皮疹和腹泻）之间的关系。群体药代动力学分析采用NONMEM方法，基于1047例接受厄洛替尼单药或联合化疗的患者的4068浓度样本进行。通过使用一阶吸收的1室模型，研究了人口统计学和临床特征对清除率和体积的影响。采用Spearman秩相关分析来检验接受单药厄洛替尼治疗的非小细胞肺癌患者最大皮疹和腹泻级别与厄洛替尼暴露之间的相关性。以厄洛替尼单药治疗的最终模型为基础，口服清除率为3.95 L/h，口服分布容积为233l，吸收率为0.95 h（-1）。在该患者群体中，厄洛替尼的中位半衰期为36.2小时。总比芬蛋白、α(1)-酸性糖蛋白和吸烟状况是影响清除率的最重要因素。目前吸烟者的清除率比曾经吸烟者或从不吸烟者快24%。药物暴露与皮疹的相关性有统计学意义（P < 0.05）。然而，在没有皮疹（分级= 0）的患者和有任何级别皮疹的患者的值范围中存在显著的重叠。暴露与腹泻之间没有明显的相关性。结论：厄洛替尼较长的半衰期支持目前每日一次150mg /d的给药方案。协变量对厄洛替尼清除率的影响以及与不良事件严重程度的相关性被提供，以帮助检测治疗紧急效应。
Objective: Our objective was to assess the pharmacokinetics of erlotinib in a large patient population with solid tumors, identify covariates, and explore relationships between exposure and safety outcomes (rash and diarrhea) in patients with non-small cell lung cancer receiving single-agent erlotinib.Methods. The population pharmacokinetic analysis was performed by use of NONMEM based on 4068 concentration samples from 1047 patients receiving erlotinib as a single agent or in combination with chemotherapy. By use of a 1-compartment model with first-order absorption, the influence of demographic and clinical characteristics on clearance and volume was examined. Spearman rank correlation analyses were performed to test for correlations between maximum grades of rash and diarrhea and erlotinib exposure in non-small cell lung cancer patients treated with single-agent erlotinib.Results. On the basis of the final model developed from patients treated with erlotinib as a single agent, the oral clearance was 3.95 L/h, the oral volume of distribution was 233 L, and the absorption rate was 0.95 h(-1). The median erlotinib half-life based on this patient population was 36.2 hours. Total biffimbin, alpha(1)-acid glycoprotein, and smoking status were the most important factors affecting clearance. The clearance in current smokers was 24% faster than that in former smokers or those who never smoked. There was a statistically significant correlation between drug exposure and rash (P < .05). However, there was significant overlap in the range of values for patients who had no rash (grade = 0) and those who had any grade of rash. No significant correlation was found between exposure and diarrhea.Conclusions: The long half-life of erlotinib supports the current once-daily dosing regimen at 150 mg/d. Effects of covariates on erlotinib clearance and correlations with adverse event severity were provided to aid in the detection of a treatment-emergent effect.