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

doi:10.2147/DDDT.S362607

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

Drug Des Devel Ther. 2022 Jul 13:16:2261-2274. doi: 10.2147/DDDT.S362607. eCollection 2022.

Authors

Chengxiao Fu^#^{1

2}, Qi Pei^#³, Wu Liang⁴, Bo Yang², Wei Li⁵, Jun Liu⁵, Hongyi Tan^{1

4}, Chengxian Guo^{1

4}, Hao Zhang⁵, Guoping Yang^{1

4}

Affiliations

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.

^# Contributed equally.

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.

Keywords: CYP3A; chronic kidney disease; nifedipine; parathyroid hormone; population pharmacokinetic.

MeSH terms

Cytochrome P-450 CYP3A* / metabolism
Humans
Models, Biological
Nifedipine
Parathyroid Hormone
Renal Insufficiency, Chronic* / drug therapy

Substances

Parathyroid Hormone
Cytochrome P-450 CYP3A
Nifedipine

Grants and funding

This work was supported by the National Major New Drug Creation Project of China (No. 2020ZX09201–010), National Scientific Foundation of China (No. 81673519), Medical Technology Innovation Guidance Project of Hunan Province Science and Technology Department (No. 2020SK51805), and Scientific Research Fund Project of Hunan Provincial Health Commission (No. 20201980).