A model analysis for dose–response relationship of warfarin in Japanese children: An introduction of the SIZE parameter

• Published in: Drug metabolism and pharmacokinetics Vol. 31; no. 3; pp. 234 - 241
• Main Authors: Nakamura, Saki, Watanabe, Nao, Yoshimura, Naoki, Ozawa, Sayaka, Hirono, Keiichi, Ichida, Fukiko, Taguchi, Masato
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2016
• Subjects: Adolescent; Anticoagulants - administration & dosage; Anticoagulants - therapeutic use; Body Weight; Bosentan; Child; Child, Preschool; Cytochrome P450 Family 4 - genetics; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Genotype; Growth and development; Humans; Japan; Japanese pediatric patients; Longitudinal Studies; Male; Models, Biological; Retrospective Studies; Sulfonamides - pharmacology; Vitamin K Epoxide Reductases - genetics; VKORC1; Warfarin; Warfarin - administration & dosage; Warfarin - therapeutic use; Japanese pediatric patients; VKORC1; Growth and development; Warfarin; Bosentan
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.1016/j.dmpk.2016.03.007

The objective of the present study was to develop an optimal equation for the pediatric dose–response relationship of warfarin using a size parameter with an exponent of body weight (SIZE) which has been proposed for scaling drug clearance. Twenty patients with stable anticoagulation by warfarin were enrolled in the present study. During a mean follow-up period of 7.36 years, 857 data points were obtained. The average patient age and body weight were 8.49 years and 24.5 kg, respectively. The relative response index to warfarin with PT-INR values normalized by daily-dose per SIZE showed fewer systematic changes than those per body weight. The anticoagulant effect of warfarin in patients with the VKORC1 1173CT or 1173CC genotype was 47.3% of that with the 1173TT genotype. Concomitant use of bosentan attenuated the anticoagulant effect of warfarin to 84.1%. In conclusion, the SIZE parameter appeared to be an effective way to describe the pediatric dose–response relationship of warfarin, and consequently, a longitudinal follow-up study design with multiple measurements was useful to detect changes within individual subjects.