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The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study
Author(s): ,
H. Maagdenberg
Affiliations:
Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
,
M. B. Bierings
Affiliations:
Department of Pediatric Hematology and Stem Cell Transplantation, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
,
C. H. Ommen
Affiliations:
Department of Pediatric Oncology/Hematology, Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands
,
F. J. M. Meer
Affiliations:
Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
,
I. M. Appel
Affiliations:
Department of Pediatric Oncology/Hematology, Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands
,
R. Y. J. Tamminga
Affiliations:
Department of Pediatric Hematology, University Medical Center Groningen, Groningen, the Netherlands
,
S. Cessie
Affiliations:
Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
,
J. J. Swen
Affiliations:
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands
,
T. Straaten
Affiliations:
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands
,
A. Boer
Affiliations:
Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
Correspondence: Anthonius de Boer, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO Box 80.082, 3508 TB, Utrecht, the Netherlands|Tel.: +31 6 027 9938|E
A. H. Maitland‐van der Zee
Affiliations:
Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands. Department of Respiratory Medicine, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands
ISTH Academy. de Boer A. Sep 4, 2018; 230978
Anthonius de Boer
Anthonius  de Boer

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Background
The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol.
Objectives
To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information.
Methods
The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow‐up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks.
Results
In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%.
Conclusions
These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.
Keyword(s)
acenocoumarol, adolescent, child, coumarins, infant, pharmacogenetics
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