Population pharmacokinetic analysis of AR-67, a lactone stable camptothecin analogue, in cancer patients with solid tumors.
Population pharmacokinetic analysis of AR-67, a lactone stable camptothecin analogue, in cancer patients with solid tumors.
复制标题
AR-67（一种内酯稳定的喜树碱类似物）在患有实体瘤的癌症患者中的群体药代动力学分析。
DOI：
10.1007/s10637-019-00744-0
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发表时间：
2019
影响因子：
3.4
通讯作者：
Leggas,Markos
中科院分区：
文献类型：
--
作者：
Tang,Fei;Tsakalozou,Eleftheria;Arnold,SusanneM;Ng,CheeM;Leggas,Markos
背景：AR-67是一种新的喜树碱类似物，处于药物开发的早期阶段。完成了对实体瘤癌症患者的1期临床试验，并建立了群体药代动力学模型(POP PK)，以便于进一步开发该研究试剂。方法利用1期临床试验收集的药代动力学数据，通过实施非线性混合效应方法，建立群体POP PK。在模型中，患者在研究开始时的特征被评估为协变量。受试者(N= 26)接受9个剂量水平的治疗(1.2-12.4g/m2/d)，每日×5次。血液学毒性数据根据暴露指标进行建模。结果两室POP PK模型最好地描述了AR-67的处置，拟合了来自25名受试者的328个PK观察。在协变量模型选择后，年龄仍然是影响中心体积的重要协变量。最终模型对药物浓度随时间变化的数据进行了较好的拟合，PK参数估计精度较高。L、L、L和L的中心容积和外周容积分别为32.2%、28.6%、6.83%和25.0%。最后，使用Emax模型进行暴露-药效学分析表明，与总剂量相比，血浆药物浓度-时间曲线是AR-67相关血液学毒性的更好的预测因子，是白细胞减少和血小板减少的更好的预测因子。结论建立了描述AR-67药代动力学的POP PK模型，并将年龄确定为显著的协变量。暴露PK指标Cmax和AUC可预测血液毒性。进一步努力确定AR-67处置的临床相关决定因素以及在更大的患者群体中的影响是有必要的。
BackgroundAR-67 is a novel camptothecin analogue at early stages of drug development. The phase 1 clinical trial in cancer patients with solid tumors was completed and a population pharmacokinetic model (POP PK) was developed to facilitate further development of this investigational agent.MethodsPharmacokinetic data collected in the phase 1 clinical trial were utilized for the development of a population POP PK by implementing the non-linear mixed effects approach. Patient characteristics at study entry were evaluated as covariates in the model. Subjects (N= 26) were treated at nine dosage levels (1.2–12.4 mg/m2/day) on a daily × 5 schedule. Hematological toxicity data were modeled against exposure metrics.ResultsA two-compartment POP PK model best described the disposition of AR-67 by fitting a total of 328 PK observations from 25 subjects. Following covariate model selection, age remained as a significant covariate on central volume. The final model provided a good fit for the concentration versus time data and PK parameters were estimated with good precision. Clearance, inter-compartmental clearance, central volume and peripheral volume were estimated to be 32.2 L/h, 28.6 L/h, 6.83 L and 25.0 L, respectively. Finally, exposure-pharmacodynamic analysis using Emaxmodels showed that plasma drug concentration versus time profiles are better predictors of AR-67-related hematologic toxicity were better predictors of leukopenia and thrombocytopenia, as compared to total dose.ConclusionsA POP PK model was developed to characterize AR-67 pharmacokinetics and identified age as a significant covariate. Exposure PK metrics Cmaxand AUC were shown to predict hematological toxicity. Further efforts to identify clinically relevant determinants of AR-67 disposition and effects in a larger patient population are warranted.