The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study
| Autor: | Maagdenberg, Hedy, Bierings, Marc B, van Ommen, C Heleen, van der Meer, Felix J M, Appel, Inge M, Tamminga, Rienk Y J, Le Cessie, Saskia, Swen, Jesse J., van der Straaten, Tahar, de Boer, Anthonius, Maitland-van der Zee, Anke H, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology |
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| Přispěvatelé: | Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Paediatric Pulmonology, APH - Personalized Medicine, Pulmonology, Pediatrics |
| Rok vydání: | 2018 |
| Předmět: |
Male
Pediatrics medicine.medical_specialty Vitamin K Body Surface Area 030204 cardiovascular system & hematology Models Biological Polymorphism Single Nucleotide 03 medical and health sciences 0302 clinical medicine Cytochrome P-450 Enzyme System medicine Journal Article Humans Thrombophilia Dosing Saliva CYP2C9 Biotransformation Genetic Association Studies Retrospective Studies pharmacogenetics Body surface area Acenocoumarol child Biological Variation Individual coumarins Dose-Response Relationship Drug business.industry acenocoumarol Warfarin Age Factors Anticoagulants Hematology infant 030220 oncology & carcinogenesis Child Preschool adolescent Cohort Practice Guidelines as Topic Female VKORC1 business Pharmacogenetics Algorithms medicine.drug Follow-Up Studies |
| Zdroj: | Journal of Thrombosis and Haemostasis, 16(9), 1732. Blackwell Publishing Ltd Journal of Thrombosis and Haemostasis, 16(9), 1732-1742 Journal of Thrombosis and Haemostasis, 16(9), 1732-1742. Wiley Journal of thrombosis and haemostasis, 16(9), 1732-1742. Wiley-Blackwell Journal of Thrombosis and Haemostasis, 16(9), 1732-1742. Wiley-Blackwell Publishing Ltd Journal of Thrombosis and Haemostasis, 16(9), 1732. Wiley-Blackwell |
| ISSN: | 1538-7933 |
| DOI: | 10.1111/jth.14211 |
| Popis: | Essentials A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45.0% of the variability in dose requirement. Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. Summary: 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. |
| Databáze: | OpenAIRE |
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