Population pharmacokinetics of ciclosporin in Chinese children with aplastic anemia: effects of weight, renal function and stanozolol administration
Abstract
Shao-qing NI1, #, Wei ZHAO2, 3, #, Jue WANG1, Su ZENG4, *, Shu-qing CHEN4, Evelyne JACQZ-AIGRAIN2, 3, Zheng-yan ZHAO5, *
1Department of Clinical Pharmacology, the Children’s Hospital of Zhejiang University School of Medicine and Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, Hangzhou 310003, China; 2Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Université Paris Diderot, Assistance Publique - Hôpitaux de Paris, Paris, France; 3Clinical Investigation Center CIC9202, INSERM, Paris, France; 4Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; 5Department of Pediatrics, the Children’s Hospital of Zhejiang University School of Medicine and Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, Hangzhou 310003, China
Aim: To develop a population pharmacokinetic model for the immunosuppressant ciclosporin in Chinese children with aplastic anemia and to identify covariates influencing ciclosporin pharmacokinetics.
Methods:A total of 102 children with either acquired or congenital aplastic anemia aged 8.8±3.6 years (range 0.9–17.6 years) were included. Therapeutic drug monitoring (TDM) data for ciclosporin were collected. The population pharmacokinetic model of ciclosporin was described using the nonlinear mixed-effects modeling (NONMEM) VI software. The final model was validated using bootstrap and normalized prediction distribution errors.
Results: A one-compartment model with first-order absorption and elimination was developed. The estimated CL/F was 15.1, which was lower than those of children receiving stem cell or kidney transplant reported in the West (16.9–29.3). The weight normalized CL/F was 0.45 (range: 0.27–0.70) L·h–1·kg–1. The covariate analysis identified body weight, serum creatinine and concomitant administration of the anabolic steroid stanozolol as individual factors influencing the CL/F of ciclosporin.
Conclusion: Our model could be used to optimize the ciclosporin dosing regimen in Chinese children with aplastic anemia.
Keywords: ciclosporin; immunosuppressant; aplastic anemia; population pharmacokinetics; stanozolol; serum creatinine; pediatrics
We thank Dingtai Ren for his great support in recording information and sample treatments and David Shen for his kindly help in our population pharmacokinetic experiments. We also sincerely thank all the participating patients and their families for their cooperation.
This work was supported by grants from the Natural Science Foundation of Zhejiang Province (Y2080183), the National Natural Science Foundation of China (81273607), the Science and Technologies Foundation of China (2009ZX09304) and the National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (2013ZX09303003). Doctor Wei Zhao and Professor Evelyne Jacqz-Aigrain received support from the European commission for their pediatric pharmacology collaborative work in China (FP7 Global research in pediatrics GRIP, grant agreement No 261060).
# The first two authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail zhaozy@zju.edu.cn (Zheng-yan ZHAO); nsqshc@gmail.com (Su ZENG)
Received 2012-10-03 Accepted 2013-01-22
Keywords:
1Department of Clinical Pharmacology, the Children’s Hospital of Zhejiang University School of Medicine and Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, Hangzhou 310003, China; 2Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Université Paris Diderot, Assistance Publique - Hôpitaux de Paris, Paris, France; 3Clinical Investigation Center CIC9202, INSERM, Paris, France; 4Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; 5Department of Pediatrics, the Children’s Hospital of Zhejiang University School of Medicine and Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, Hangzhou 310003, China
Aim: To develop a population pharmacokinetic model for the immunosuppressant ciclosporin in Chinese children with aplastic anemia and to identify covariates influencing ciclosporin pharmacokinetics.
Methods:A total of 102 children with either acquired or congenital aplastic anemia aged 8.8±3.6 years (range 0.9–17.6 years) were included. Therapeutic drug monitoring (TDM) data for ciclosporin were collected. The population pharmacokinetic model of ciclosporin was described using the nonlinear mixed-effects modeling (NONMEM) VI software. The final model was validated using bootstrap and normalized prediction distribution errors.
Results: A one-compartment model with first-order absorption and elimination was developed. The estimated CL/F was 15.1, which was lower than those of children receiving stem cell or kidney transplant reported in the West (16.9–29.3). The weight normalized CL/F was 0.45 (range: 0.27–0.70) L·h–1·kg–1. The covariate analysis identified body weight, serum creatinine and concomitant administration of the anabolic steroid stanozolol as individual factors influencing the CL/F of ciclosporin.
Conclusion: Our model could be used to optimize the ciclosporin dosing regimen in Chinese children with aplastic anemia.
Keywords: ciclosporin; immunosuppressant; aplastic anemia; population pharmacokinetics; stanozolol; serum creatinine; pediatrics
We thank Dingtai Ren for his great support in recording information and sample treatments and David Shen for his kindly help in our population pharmacokinetic experiments. We also sincerely thank all the participating patients and their families for their cooperation.
This work was supported by grants from the Natural Science Foundation of Zhejiang Province (Y2080183), the National Natural Science Foundation of China (81273607), the Science and Technologies Foundation of China (2009ZX09304) and the National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (2013ZX09303003). Doctor Wei Zhao and Professor Evelyne Jacqz-Aigrain received support from the European commission for their pediatric pharmacology collaborative work in China (FP7 Global research in pediatrics GRIP, grant agreement No 261060).
# The first two authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail zhaozy@zju.edu.cn (Zheng-yan ZHAO); nsqshc@gmail.com (Su ZENG)
Received 2012-10-03 Accepted 2013-01-22