Drug Res (Stuttg) 2022; 72(01): 23-33
DOI: 10.1055/a-1581-7609
Original Article

Maxacalcitol Pharmacokinetic–Pharmacodynamic Modeling and Simulation for Secondary Hyperparathyroidism in Patients Receiving Maintenance Hemodialysis

Mizuki Fukazawa-Shinotsuka
1   Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Tomohisa Saito
1   Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Masaichi Abe
1   Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Satofumi Iida
1   Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
I-Ting Wang
2   Chugai Pharma Taiwan Ltd, Taipei, Taiwan
,
Kimio Terao
1   Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Hsi-Hsien Chen
3   Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
,
Ming-Che Liu
4   Clinical Research Center, Taipei Medical University Hospital, Taipei, Taiwan
5   School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
› Author Affiliations

Abstract

Background Maxacalcitol was approved in Taiwan in 2018 as the first active vitamin D3 injection for secondary hyperparathyroidism (SHPT) in patients on maintenance hemodialysis. However, no data from any clinical study with maxacalcitol in Taiwanese patients is available.

Objectives This analysis aimed to evaluate the profiles of parathyroid hormone (PTH) and calcium (Ca) concentrations in Taiwanese SHPT patients on hemodialysis and maxacalcitol.

Methods We developed population pharmacokinetic (PK) and pharmacodynamic (PD) models using a modeling and simulation approach. The data for these analyses were obtained from two studies: a clinical pharmacology study in Japanese patients and an ethnic comparison study in healthy Japanese and -Taiwanese volunteers. We then conducted a simulation study with a PK-PD model comprising the PK and PD models developed here.

Results Serum maxacalcitol concentration profile was modeled using a two-compartment model that took into consideration the distribution of concentrations below the lower limit of quantification. An ethnic difference in clearance was included in the PK model as a covariate. A PD model that used a PTH/Ca feedback loop best described the observed data. There were no significant differences in Ca or PTH concentrations between Taiwanese and Japanese based on the simulation results from our PK-PD model, even though maxacalcitol exposure was approximately 40% higher in Taiwanese than in Japanese.

Conclusions On the basis of these population PK and PD analyses and the clinical study conducted in Japan, there is no clinically relevant difference between Taiwanese and Japanese in terms of serum Ca or PTH levels.



Publication History

Received: 22 April 2021

Accepted: 03 August 2021

Article published online:
06 September 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag
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  • References

  • 1 Chugai Pharmaceutical Co. L. OXAROL® Injection package insert version 7. revised October 2015
  • 2 Liu M-C, Chou F-Y, Chien Y-A. et al. Comparative pharmacokinetics of maxacalcitol in healthy Taiwanese and Japanese subjects. Heliyon 2020; 6: e03538-e03538 doi:10.1016/j.heliyon.2020.e03538
  • 3 Miyataka K, Ohnuki M, Ohyama N. et al. Clinical efficacy of 22-oxacalcitriol against secondary hyperparathyroidism in hemodialysis patients. Nihon Toseki Igakkai Zasshi 1999; 32: 1079-1083 doi:10.4009/jsdt.32.1079
  • 4 Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn 2001; 28: 481-504 doi:10.1023/a:1012299115260
  • 5 Bergstrand M, Hooker AC, Wallin JE. et al. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. Aaps j 2011; 13: 143-151 doi:10.1208/s12248-011-9255-z
  • 6 Thai HT, Mentré F, Holford NH. et al. Evaluation of bootstrap methods for estimating uncertainty of parameters in nonlinear mixed-effects models: A simulation study in population pharmacokinetics. J Pharmacokinet Pharmacodyn 2014; 41: 15-33 doi:10.1007/s10928-013-9343-z
  • 7 Chen P, Narayanan A, Wu B. et al. Population Pharmacokinetic and Pharmacodynamic Modeling of Etelcalcetide in Patients with Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis. Clin Pharmacokinet 2018; 57: 71-85 doi:10.1007/s40262-017-0550-4
  • 8 Chen P, Olsson Gisleskog P, Perez-Ruixo JJ. et al. Population Pharmacokinetics and Pharmacodynamics of the Calcimimetic Etelcalcetide in Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis. CPT Pharmacometrics Syst Pharmacol 2016; 5: 484-494 doi:10.1002/psp4.12106
  • 9 Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 2008; 48: 303-332 doi:10.1146/annurev.pharmtox.48.113006.094708
  • 10 Beto J, Bhatt N, Gerbeling T. et al. Overview of the 2017 KDIGO CKD-MBD Update: Practice Implications for Adult Hemodialysis Patients. J Ren Nutr 2019; 29: 2-15 doi:10.1053/j.jrn.2018.05.006
  • 11 Institutes NHR. Taiwan Chronic Kidney Disease Clinical Guidelines. 2015
  • 12 Japanese Society of N. Evidence-based Clinical Practice Guideline for CKD 2013. Clinical and Experimental Nephrology 2014; 18: 346-423 doi:10.1007/s10157-014-0949-2
  • 13 Sato K, Tominaga Y, Ichikawa F. et al. In vitro suppression of parathyroid hormone secretion by 22-oxa-calcitriol in human parathyroid hyperplasia due to uraemia. Nephrology 2008; 4: 177-182 doi:10.1046/j.1440-1797.1998.d01-28.x