■甲状旁腺激素(PTH)可以诱导慢性肾脏病(CKD)中CYP3A的下调。然而,从临床角度来看,PTH对CYP3A介导的清除途径的影响尚不清楚.
■本研究采用群体药代动力学(PopPK)模型来描绘CKD患者CYP3A活性的潜在变化。硝苯地平的药代动力学数据,典型的CYP3A底物,以及协变量信息,前瞻性地从157名患者中收集,总共612个浓度。使用非线性混合效应模型进行PopPK数据分析。
■硝苯地平的药代动力学是根据具有零级吸收和一级消除的一室模型进行最佳描述的。估计的群体参数(和个体间变异性)是表观清除率(CL/F)49.61L/h(58.33%)和表观分布体积(V/F)2300.26L(45.62%),PTH水平与CL/F呈负相关。与参考水平相比,观察到硝苯地平的剂量应随着PTH的最大边界值而减少,在蒙特卡罗模拟之后。
■本研究深入了解了PTH对CYP3A介导的清除途径的影响。此外,PTH可作为CKD患者合适给药CYP3A消除药物的指导。
UNASSIGNED: Parathyroid hormone (PTH) can induce the downregulation of
CYP3A in chronic kidney disease (CKD). Nevertheless, the effect of PTH on
CYP3A-mediated clearance pathways from a clinical perspective remains unclear.
UNASSIGNED: This study employed population pharmacokinetic (PopPK) modeling to delineate potential changes in
CYP3A activity in patients with CKD. Pharmacokinetic data for nifedipine, a typical
CYP3A substrate, as well as covariate information, were prospectively collected from 157 patients with a total of 612 concentrations. PopPK data analysis was performed using a nonlinear mixed-effects model.
UNASSIGNED: The pharmacokinetics of nifedipine were optimally described according to a one-compartment model with zero-order absorption and first-order elimination. The estimated population parameters (and interindividual variability) were apparent clearance (CL/F) 49.61 L/h (58.33%) and apparent volume of distribution (V/F) 2300.26 L (45.62%), and the PTH level negatively correlated with CL/F. In comparison with the reference level, it was observed that the dosage of nifedipine should be reduced with the maximum boundary value of PTH, after a Monte Carlo simulation.
UNASSIGNED: This study provides insight into the effects of PTH on
CYP3A-mediated clearance pathways. Moreover, PTH could be used as a guide for the appropriate administration of CYP3A eliminated drugs in patients with CKD.