Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, PR China; Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
J Pharm Sci. 2018 May;107(5):1454-1460. doi: 10.1016/j.xphs.2018.01.004. Epub 2018 Jan 10.
The intra- and inter-individual variances of methotrexate (MTX) pharmacokinetics are extremely large, and the pharmacokinetic property of MTX in patients with primary central nervous system lymphoma (PCNSL) is unestablished. A total of 701 MTX plasma concentrations from 98 patients with PCNSL under high-dose MTX therapy were used to develop the population pharmacokinetic (popPK) model of MTX by using the nonlinear mixed-effects modeling method. A 2-compartment model was employed to describe the pharmacokinetic property of MTX. In the final popPK model, inclusion of serum creatinine and body surface area significantly reduced objective function value for clearance over the base model (p <0.001), and inclusion of age significantly reduced objective function value for distribution volume of central compartment (V) over the base model (p <0.001). In the final popPK model, the inter-individual clearance = 6.67 × (SCR/68.1) × (BSA/1.75); V = 24.46 × (age/57.16). The precision of all parameters was acceptable (relative standard error <28.61%). Bootstrap and visual predictive check results indicated that the final popPK model was stable with acceptable predictive ability. The popPK model may be useful for personalized medication in PCNSL patients under high-dose MTX therapy. Further studies are warranted to confirm the results.
MTX 药代动力学的个体内和个体间差异极大，且原发性中枢神经系统淋巴瘤（PCNSL）患者的 MTX 药代动力学特征尚未确定。本研究采用非线性混合效应模型法，共纳入 98 例接受大剂量 MTX 治疗的 PCNSL 患者的 701 个 MTX 血药浓度数据，建立 MTX 的群体药代动力学（popPK）模型。采用 2 室模型描述 MTX 的药代动力学特征。在最终的 popPK 模型中，纳入血清肌酐和体表面积可显著降低清除率的目标函数值（相对于基础模型，p<0.001），纳入年龄可显著降低中央室分布容积（V）的目标函数值（相对于基础模型，p<0.001）。在最终的 popPK 模型中，个体间清除率=6.67×（SCR/68.1）×（BSA/1.75）；V=24.46×（年龄/57.16）。所有参数的精度均可以接受（相对标准误差<28.61%）。Bootstrap 和可视化预测检查结果表明，最终的 popPK 模型稳定，具有可接受的预测能力。该 popPK 模型可能有助于对接受大剂量 MTX 治疗的 PCNSL 患者进行个体化用药。需要进一步的研究来验证该结果。
