Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Boston, MA, USA.
Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
J Clin Pharmacol. 2019 Jan;59(1):112-122. doi: 10.1002/jcph.1295. Epub 2018 Aug 13.
Selumetinib (AZD6244, ARRAY-142886) is a mitogen-activated protein kinase kinase inhibitor that has been tested for treatment of non-small cell lung cancer (NSCLC). Selumetinib (75 mg twice daily) plus docetaxel in patients with advanced NSCLC has been assessed in phase 2 (SELECT-2) and phase 3 (SELECT-1) clinical trials. The objective of the current analysis was to investigate the exposure-response relationship of selumetinib in these 2 clinical trials, based on the development of a population pharmacokinetic (PopPK) model for selumetinib and its active metabolite, N-desmethyl selumetinib, in patients with NSCLC. A PopPK model using data from seven phase 1 studies was first developed and served as prior information for the development of the patient PopPK model. The pharmacokinetics (PK) of selumetinib and N-desmethyl selumetinib were modeled simultaneously. A two-compartment model with zero-first order absorption and first-order elimination reasonably described the selumetinib PK. The N-desmethyl metabolite of selumetinib was described by a one-compartment model with first-order elimination. The final PK parameter estimates were similar between patients with NSCLC and patients in the phase 1 population. Selumetinib apparent clearance and central volume of distribution were 11.9 L/h and 32.1 L, respectively, in patients. Individual selumetinib exposure metrics were estimated to investigate the correlation between exposure and efficacy/safety endpoints observed in NSCLC studies. There was no significant difference in progression-free survival (the primary endpoint) among the different quartiles of exposure. Similarly, no significant correlation was observed between selumetinib exposure and other secondary efficacy or safety endpoints. The conclusions are in accordance with the reported clinical findings.
色瑞替尼（AZD6244，ARRAY-142886）是一种丝裂原活化蛋白激酶激酶抑制剂，已被用于治疗非小细胞肺癌（NSCLC）。在晚期 NSCLC 患者中，色瑞替尼（75mg 每日两次）联合多西他赛已在 2 期（SELECT-2）和 3 期（SELECT-1）临床试验中进行了评估。目前分析的目的是根据 NSCLC 患者中色瑞替尼及其活性代谢物 N-去甲基色瑞替尼的群体药代动力学（PopPK）模型，研究这 2 项临床试验中色瑞替尼的暴露-反应关系。首先开发了一个基于 7 项 1 期研究数据的 PopPK 模型，作为患者 PopPK 模型开发的先验信息。同时对色瑞替尼和 N-去甲基色瑞替尼的药代动力学（PK）进行建模。零级-一级吸收和一级消除的两室模型合理地描述了色瑞替尼 PK。色瑞替尼的 N-去甲基代谢物通过一级消除的一室模型来描述。最终 PK 参数估计在 NSCLC 患者和 1 期人群中的患者之间是相似的。患者中色瑞替尼的表观清除率和中央分布容积分别为 11.9 L/h 和 32.1 L。个体色瑞替尼暴露指标用于评估 NSCLC 研究中观察到的暴露与疗效/安全性终点之间的相关性。不同暴露四分位组之间的无进展生存期（主要终点）没有显著差异。同样，也没有观察到色瑞替尼暴露与其他次要疗效或安全性终点之间存在显著相关性。结论与报道的临床发现一致。
