Guglieri-López Beatriz, Pérez-Pitarch Alejandro, Moes Dirk Jan A R, Porta-Oltra Begoña, Climente-Martí Mónica, Guchelaar Henk Jan, Merino-Sanjuán Matilde
Pharmacy Department, Doctor Peset University Hospital of Valencia, Gaspar Aguilar Avenue, 90, 46017, Valencia, Spain.
Pharmacy Department, University Clinical Hospital of Valencia, Blasco Ibañez Avenue, 17, 46010, Valencia, Spain.
Cancer Chemother Pharmacol. 2017 Jan;79(1):189-200. doi: 10.1007/s00280-016-3228-y. Epub 2016 Dec 30.
Lenalidomide disease-specific toxicity profiles and potentially life-threatening adverse events support the consideration of diversity in starting doses. The aim of this study was to conduct a population pharmacokinetic analysis of lenalidomide in multiple myeloma patients to identify and evaluate non-studied covariates that could be used for dose individualization.
Blood samples were collected from 15 multiple myeloma patients. Nonlinear mixed-effects modeling was used to develop a population pharmacokinetic model and perform covariate analysis. The developed model was used to simulate dose schedules in order to explore the need of different dosing regimens in patients with different covariate values.
The data were accurately described by a one-compartment model with first-order elimination. Absorption was best described using three transit compartments. Creatinine clearance and body surface area were identified as covariates affecting apparent clearance and apparent volume of distribution, respectively. Simulations revealed that lower starting doses than the standard 25 mg/daily could be used in patients with body surface area below 1.8 m and even higher doses might be necessary for patients with normal renal function and large body surface area.
This study identified creatinine clearance and body surface area as covariates that have a clinically relevant impact on lenalidomide pharmacokinetics using population pharmacokinetics. In addition, the developed population pharmacokinetic model can be used to individualize lenalidomide dose in multiple myeloma patients, taking into account not only creatinine clearance but also body surface area.
来那度胺的疾病特异性毒性特征和潜在的危及生命的不良事件支持考虑起始剂量的多样性。本研究的目的是对多发性骨髓瘤患者进行来那度胺的群体药代动力学分析，以识别和评估可用于剂量个体化的未研究协变量。
从15例多发性骨髓瘤患者中采集血样。采用非线性混合效应模型建立群体药代动力学模型并进行协变量分析。所建立的模型用于模拟给药方案，以探讨不同协变量值患者对不同给药方案的需求。
数据用具有一级消除的单室模型准确描述。吸收用三个转运室描述最佳。肌酐清除率和体表面积分别被确定为影响表观清除率和表观分布容积的协变量。模拟结果显示，体表面积低于1.8 m²的患者可使用低于标准的25 mg/日的起始剂量，而肾功能正常且体表面积大的患者可能需要更高的剂量。
本研究使用群体药代动力学确定肌酐清除率和体表面积为对来那度胺药代动力学有临床相关影响的协变量。此外，所建立的群体药代动力学模型可用于多发性骨髓瘤患者来那度胺剂量的个体化，不仅要考虑肌酐清除率，还要考虑体表面积。
