Evaluation of the effects of ontogenetic or maturation functions and chronic heart failure on the model analysis for the dose-response relationship of warfarin in Japanese children

  • Rika Tamura
  • Nao Watanabe
  • Saki Nakamura
  • Naoki Yoshimura
  • Sayaka Ozawa
  • Keiichi Hirono
  • Fukiko Ichida
  • Masato TaguchiEmail author
Pharmacokinetics and Disposition



We previously demonstrated that the rational pediatric dosage of warfarin can be well-described by a SIZE parameter that includes an allometry exponent of weight. On the other hand, allometry alone is considered to be insufficient to predict drug clearance in neonates and infants. The primary purpose of the present study was to evaluate the effects of incorporation of the maturation process into the analysis model for the dose-response relationship of warfarin in Japanese children. In addition, we evaluated the effect of chronic heart failure (CHF) on the response to warfarin as an independent risk factor for increased anticoagulant effects.


Thirty-eight patients with stable anticoagulation by warfarin were enrolled. During a mean follow-up period of 4.74 ± 3.51 years, 1092 data points including prothrombin time-international normalized ratio (PT-INR) were obtained. The data were subjected to multiple regression analysis to identify covariates related to the anticoagulant effects.


Two different models describing the maturation process did not improve the predictive performance for the dose-response relationship in pediatric patients. In addition to the SIZE-normalized daily dose, the vitamin K epoxide reductase complex 1 (VKORC1) genotype, and concomitant use of bosentan, CHF was identified as a covariate increasing the anticoagulant effects of warfarin to 118%.


The SIZE parameter was useful even without incorporation of maturation models to describe the response to warfarin in pediatric patients, and our longitudinal follow-up study design with multiple observations was beneficial to detect changes within individual subjects.


Anticoagulant effect Warfarin Allometry Heart failure Maturation process Children 


Funding information

This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Sciences (JSPS) and from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).

Compliance with ethical standards

This research involved human subject participants. All patients and/or parents gave written informed consent to participate in the present study, which was approved by the ethics committee of the University of Toyama.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

228_2019_2652_MOESM1_ESM.pptx (229 kb)
ESM 1 (PPTX 228 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan

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