Chengxiao Fu1,2, Qi Pei3, Wu Liang4, Bo Yang2, Wei Li5, Jun Liu5, Hongyi Tan1,4, Chengxian Guo1,4, Hao Zhang5, Guoping Yang1,4. 1. Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China. 2. The First Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, People's Republic of China. 3. Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China. 4. Research Center of Drug Clinical Evaluation of Central South University, Changsha, People's Republic of China. 5. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China.
Abstract
Purpose: 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.
Purpose: 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.
Authors: Linh Nguyen; Jaymes Holland; David Ramies; Richard Mamelok; Natacha Benrimoh; Sabrina Ciric; Thomas Marbury; Richard A Preston; Douglas M Heuman; Edith Gavis; Steven Lacy Journal: J Clin Pharmacol Date: 2016-03-23 Impact factor: 3.126