Population Pharmacokinetic Modelling for Nifedipine to Evaluate the Effect of Parathyroid Hormone on CYP3A in Patients with Chronic Kidney Disease.

Chengxiao Fu, Qi Pei, Wu Liang, Bo Yang, Wei Li, Jun Liu, Hongyi Tan, Chengxian Guo, Hao Zhang, Guoping Yang

Drug design, development and therapy 2022

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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. 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. 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. 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. © 2022 Fu et al.

Citation

Chengxiao Fu, Qi Pei, Wu Liang, Bo Yang, Wei Li, Jun Liu, Hongyi Tan, Chengxian Guo, Hao Zhang, Guoping Yang. Population Pharmacokinetic Modelling for Nifedipine to Evaluate the Effect of Parathyroid Hormone on CYP3A in Patients with Chronic Kidney Disease. Drug design, development and therapy. 2022;16:2261-2274