Lu Jian-Feng, Eppler Steve M, Wolf Julie, Hamilton Marta, Rakhit Ashok, Bruno Rene, Lum Bert L
Pharmacokinetic and Pharmacodynamic Sciences, Genentech, South San Francisco, CA 94080, USA.
Clin Pharmacol Ther. 2006 Aug;80(2):136-45. doi: 10.1016/j.clpt.2006.04.007.
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.
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.
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 bilirubin, alpha1-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.
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.
我们的目的是评估厄洛替尼在大量实体瘤患者中的药代动力学，识别协变量，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量与安全性结局（皮疹和腹泻）之间的关系。
基于1047例接受厄洛替尼单药治疗或联合化疗患者的4068份血药浓度样本，使用NONMEM进行群体药代动力学分析。采用具有一级吸收的单室模型，研究人口统计学和临床特征对清除率和血药浓度的影响。进行Spearman等级相关分析，以检验接受单药厄洛替尼治疗的非小细胞肺癌患者皮疹和腹泻的最高等级与厄洛替尼暴露量之间的相关性。
基于以厄洛替尼单药治疗患者建立的最终模型，口服清除率为3.95 L/h，口服分布容积为233 L，吸收速率为0.95 h(-1)。基于该患者群体，厄洛替尼的中位半衰期为36.2小时。总胆红素、α1-酸性糖蛋白和吸烟状态是影响清除率的最重要因素。当前吸烟者的清除率比既往吸烟者或从不吸烟者快24%。药物暴露量与皮疹之间存在统计学显著相关性（P < 0.05）。然而，无皮疹（0级）患者和有任何等级皮疹患者的数值范围有显著重叠。未发现暴露量与腹泻之间存在显著相关性。
厄洛替尼的长半衰期支持目前每日150 mg的给药方案。提供了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，以帮助检测治疗中出现的效应。
