Castro-Suárez Niurys de, Trame Mirjam N, Ramos-Suzarte Mayra, Dávalos José M, Bacallao-Mendez Raymed A, Maceo-Sinabele Anaelys R, Mangas-Sanjuán Víctor, Reynaldo-Fernández Gledys, Rodríguez-Vera Leyanis
Pharmacy Department, Institute of Food and Pharmacy, University of Havana,Havana 11300, Cuba.
AVROBIO Inc., Department of Translational Data Sciences and Advanced Analytics, Cambridge, MA 02139, USA.
Pharmaceutics. 2020 Nov 26;12(12):1147. doi: 10.3390/pharmaceutics12121147.
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression of epidermal growth factor receptor (EGFR). Nimotuzumab is a recombinant humanized monoclonal antibody against human EGFR. The aim of this study was to develop a population pharmacokinetic model for nimotuzumab and to identify demographic and clinical predictive factors of the pharmacokinetic variability. The population pharmacokinetics (PopPK) of nimotuzumab was characterized using a nonlinear mixed-effect modeling approach with NONMEM. A total of 422 log-transformed concentration-versus-time datapoints from 20 patients enrolled in a single-center phase I clinical trial were used. Quasi steady state approximation of the full TMDD (target-mediated drug disposition) model with constant target concentration best described the concentration-time profiles. A turnover mediator was included which stimulates the non-specific clearance of mAb in the central compartment in order to explain the reduced levels at higher doses. Covariates had no influence on the PK (pharmacokinetics) parameters. The model was able to detect that the maximum effective dose in ADPKD subjects is 100 mg. The developed PopPK model may be used to guide the dose selection for nimotuzumab during routine clinical practice in patients with polycystic kidney disease. The model will further support the ongoing investigations of the PK/PD relationships of nimotuzumab to improve its therapeutic use in other disease areas.
常染色体显性多囊肾病（ADPKD）是一种以表皮生长因子受体（EGFR）过度表达为特征的遗传疾病。尼妥珠单抗是一种针对人EGFR的重组人源化单克隆抗体。本研究的目的是建立尼妥珠单抗的群体药代动力学模型，并确定药代动力学变异性的人口统计学和临床预测因素。采用非线性混合效应建模方法和NONMEM对尼妥珠单抗的群体药代动力学（PopPK）进行表征。使用了来自一项单中心I期临床试验的20名患者的总共422个对数转换后的浓度-时间数据点。具有恒定靶浓度的完整TMDD（靶介导药物处置）模型的准稳态近似最能描述浓度-时间曲线。纳入了一个周转介质，以刺激中央室中mAb的非特异性清除，从而解释较高剂量下水平的降低。协变量对PK（药代动力学）参数没有影响。该模型能够检测到ADPKD受试者的最大有效剂量为100mg。所建立的PopPK模型可用于指导多囊肾病患者常规临床实践中尼妥珠单抗的剂量选择。该模型将进一步支持正在进行的尼妥珠单抗PK/PD关系研究，以改善其在其他疾病领域的治疗应用。
