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

Chengxiao Fu,1,2,* Qi Pei,3,* Wu Liang,4 Bo Yang,2 Wei Li,5 Jun Liu,5 Hongyi Tan,1,4 Chengxian Guo,1,4 Hao Zhang,5 Guoping Yang1,4 1Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2The First Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, People’s Republic of China; 3Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Research Center of Drug Clinical Evaluation of Central South University, Changsha, People’s Republic of China; 5Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guoping Yang; Hao Zhang, Email ygp9880@126.com; zhanghaoliaoqing@163.comPurpose: 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.Methods: 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.Results: 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.Conclusion: 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.Keywords: chronic kidney disease, parathyroid hormone, CYP3A, population pharmacokinetic, nifedipine