Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Geneva, Switzerland; Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Clin Ther. 2020 Jul;42(7):1302-1316. doi: 10.1016/j.clinthera.2020.05.008. Epub 2020 Jul 4.
Erlotinib is an oral first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for non-small cell lung cancers (NSCLC) with EGFR-activating mutations. Older patients experience more toxicities compared with younger patients at the standard recommended dose of 150 mg once daily. The aims of this study were to describe the pharmacokinetic profile of erlotinib in unselected patients with NSCLC, to quantify and explain its variability, to challenge the standard recommended dose in older patients, and to propose clinical recommendations for the therapeutic management of patients taking erlotinib.
A population pharmacokinetic model was developed using erlotinib plasma concentrations collected from patients with NSCLC participating in a routine therapeutic drug monitoring program (with the nonlinear mixed effect modeling program NONMEM). Relevant demographic characteristics, clinical factors, and co-medications were tested as potential covariates. An independent dataset was used for model validation. Simulations based on the final model allowed comparison of expected erlotinib concentrations under standard and alternative dosing regimens for smokers and for several age groups.
A total of 481 erlotinib plasma concentrations from 91 patients with NSCLC were used for model building and 239 plasma drug concentrations from 107 patients for model validation. A one-compartment model with first-order absorption and elimination provided the best fit. Average erlotinib CL/F with interindividual variability (%CV) was 3.8 L/h (41.5%), and V/F was 166 L (53.8%). The absorption rate constant was 1.48 h. The external validation showed a negligible bias of -4% (95% CI, -7 to -1) in the individual predictions, with a precision of 23%. Current smoking and use of proton pump inhibitors were associated with higher CL/F, whereas age was associated with lower CL/F. Simulations suggest that a lower dose in older patients would decrease the risk of overexposure.
This large cohort study confirms the substantial interindividual variability in erlotinib plasma exposure and the impact of smoking and proton pump inhibitor intake. This large variability in erlotinib pharmacokinetics indicates that the standard recommended dose of 150 mg once daily is likely not appropriate to reach the expected concentrations in each patient. Concentration monitoring should be performed to individually adjust the erlotinib dosing regimen. The observed decrease in erlotinib CL/F with age suggests that a lower starting daily dose of 100 mg with concentration-guided dose adjustment would prevent overexposure and potential toxicity in older frail patients with co-morbidities.
厄洛替尼是一种口服第一代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，适用于具有 EGFR 激活突变的非小细胞肺癌（NSCLC）。与标准推荐剂量为 150mg 每日一次的年轻患者相比，老年患者的毒性反应更多。本研究的目的是描述 NSCLC 患者中厄洛替尼的药代动力学特征，量化并解释其变异性，挑战老年患者的标准推荐剂量，并提出接受厄洛替尼治疗的患者的治疗管理临床建议。
使用来自参加常规治疗药物监测计划的 NSCLC 患者的厄洛替尼血浆浓度，使用非线性混合效应建模程序 NONMEM 建立群体药代动力学模型。测试了相关的人口统计学特征、临床因素和合并用药作为潜在的协变量。使用独立数据集进行模型验证。基于最终模型的模拟允许比较标准和替代给药方案下吸烟者和几个年龄组的预期厄洛替尼浓度。
共使用来自 91 例 NSCLC 患者的 481 个厄洛替尼血浆浓度进行模型构建，使用来自 107 例患者的 239 个血浆药物浓度进行模型验证。具有一级吸收和消除的单室模型提供了最佳拟合。个体间变异性（%CV）的厄洛替尼 CL/F 平均为 3.8 L/h（41.5%），V/F 为 166 L（53.8%）。吸收速率常数为 1.48 h。外部验证显示个体预测的偏差可忽略不计（-4%，95%CI，-7 至-1），精度为 23%。目前吸烟和质子泵抑制剂的使用与更高的 CL/F 相关，而年龄与更低的 CL/F 相关。模拟表明，老年患者的较低剂量可能会降低过度暴露的风险。
这项大型队列研究证实了厄洛替尼血浆暴露的个体间存在大量变异性，以及吸烟和质子泵抑制剂摄入的影响。厄洛替尼药代动力学的这种大量变异性表明，标准推荐剂量 150mg 每日一次可能无法达到每个患者的预期浓度。应进行浓度监测以单独调整厄洛替尼给药方案。观察到的随着年龄的增长而降低的厄洛替尼 CL/F 表明，对于合并症的虚弱老年患者，较低的起始每日剂量 100mg 并进行浓度指导的剂量调整将防止过度暴露和潜在毒性。
