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
- 53 Downloads
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.
KeywordsAnticoagulant effect Warfarin Allometry Heart failure Maturation process Children
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.
- 6.Takahashi H, Wilkinson GR, Nutescu EA, Morita T, Ritchie MD, Scordo MG, Pengo V, Barban M, Padrini R, Ieiri I, Otsubo K, Kashima T, Kimura S, Kijima S, Echizen H (2006) Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 16:101–110CrossRefGoogle Scholar
- 15.Beal SL, Boeckmann AJ, Sheiner LB (1992) NONMEM Users Guides: NONMEM project group. University of California, San FranciscoGoogle Scholar
- 17.Hamberg AK, Friberg LE, Hanséus K, Ekman-Joelsson BM, Sunnegårdh J, Jonzon A, Lundell B, Jonsson EN, Wadelius M (2013) Warfarin dose prediction in children using pharmacometric bridging--comparison with published pharmacogenetic dosing algorithms. Eur J Clin Pharmacol 69(6):1275–1283CrossRefGoogle Scholar
- 24.O'Reilly RA, Aggeler PM (1970) Determinants of the response to oral anticoagulant drugs in man. Pharmacol Rev 22(1):35–96Google Scholar
- 26.Verstraete M, Verwilghen R (1980) Haematological disorders. 2nd ed. In: Avery GS (ed) Drug treatment. Churchill Livingstone, Edinburgh, pp 889–952Google Scholar