Australian Centre for Pharmacometrics, School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Australia.
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Br J Clin Pharmacol. 2019 May;85(5):924-934. doi: 10.1111/bcp.13873. Epub 2019 Feb 27.
Lenalidomide is an immunomodulatory imide drug used broadly in the treatment of multiple myeloma and lymphoma. It continues to be evaluated in chronic lymphocytic leukaemia (CLL) at lower doses due to dose-related toxicities including tumour flare and tumour lysis syndrome. This study aimed to develop a population pharmacokinetic model for lenalidomide in multiple cancers, including CLL, to identify any disease-related differences in disposition.
Lenalidomide concentrations from 4 clinical trials were collated (1999 samples, 125 subjects), covering 4 cancers (multiple myeloma, CLL, acute myeloid leukaemia and acute lymphoblastic leukaemia) and a large dose range (2.5-75 mg). A population pharmacokinetic model was developed with NONMEM and patient demographics were tested as covariates.
The data were best fitted by a 1-compartment kinetic model with absorption described by 7 transit compartments. Clearance and volume of distribution were allometrically scaled for fat-free mass. The population parameter estimates for apparent clearance, apparent volume of distribution and transit rate constant were 12 L/h (10.8-13.6), 68.8 L (61.8-76.3), and 13.5 h (11.9-36.8) respectively. Patients with impaired renal function (creatinine clearance <30 mL/min) exhibited a 22% reduction in lenalidomide clearance compared to patients with creatinine clearance of 90 mL/min. Cancer type had no discernible effect on lenalidomide disposition.
This is the first report of a lenalidomide population pharmacokinetic model to evaluate lenalidomide pharmacokinetics in patients with CLL and compare its pharmacokinetics with other B-cell malignancies. As no differences in pharmacokinetics were found between the observed cancer-types, the unique toxicities observed in CLL may be due to disease-specific pharmacodynamics.
来那度胺是一种免疫调节亚胺药物，广泛用于多发性骨髓瘤和淋巴瘤的治疗。由于剂量相关的毒性，包括肿瘤爆发和肿瘤溶解综合征，在较低剂量下继续在慢性淋巴细胞白血病（CLL）中进行评估。本研究旨在开发一种用于多种癌症（包括 CLL）的来那度胺群体药代动力学模型，以确定任何与疾病相关的处置差异。
汇集了来自 4 项临床试验的来那度胺浓度（1999 个样本，125 名受试者），涵盖了 4 种癌症（多发性骨髓瘤、CLL、急性髓细胞白血病和急性淋巴细胞白血病）和广泛的剂量范围（2.5-75mg）。使用 NONMEM 开发了一个群体药代动力学模型，并测试了患者人口统计学数据作为协变量。
数据最好通过一个 1 室动力学模型拟合，吸收通过 7 个转运室描述。清除率和分布容积按去脂体重进行比例缩放。表观清除率、表观分布容积和转运速率常数的群体参数估计值分别为 12L/h（10.8-13.6）、68.8L（61.8-76.3）和 13.5h（11.9-36.8）。肾功能受损（肌酐清除率<30mL/min）的患者与肌酐清除率为 90mL/min 的患者相比，来那度胺清除率降低了 22%。癌症类型对来那度胺处置没有明显影响。
这是首个报告来那度胺群体药代动力学模型的研究，用于评估来那度胺在 CLL 患者中的药代动力学，并比较其药代动力学与其他 B 细胞恶性肿瘤。由于观察到的癌症类型之间没有药代动力学差异，CLL 中观察到的独特毒性可能是由于疾病特异性药效学。
