The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study

Abstract

To cite this article: Maagdenberg H, Bierings MB, van Ommen CH, van der Meer FJM, Appel IM, Tamminga RYJ, le Cessie S, Swen JJ, van der Straaten T, de Boer A, Maitland-van der Zee AH. The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study. J Thromb Haemost 2018; https://doi.org/10.1111/jth.14211. 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.

Considerations for Implementing Precision Therapeutics for Children

“…Several studies of the pharmacogenetics of the response to vitamin K antagonists in children have been published since 2010 and consistently have reported that children with vitamin K oxidoreductase complex 1 (VKORC1) ‐1639AA genotypes require significantly lower doses of warfarin to achieve the same target INR as children with VKORC1 ‐1639GG genotypes, similar to the results of adult studies . However, what is highly inconsistent among the pediatric studies is the relative importance of genetic (primarily VKORC1 and CYP2C9 genotype) and nongenetic/”developmental” factors as determinants of variability in the warfarin dose required to achieve a stable target INR.…”

“…23 A recently published study of acenocoumarol in Dutch children found the presence of a Fontan circulation to account for 17.3% of the variability in the dose required to achieve the target INR, and confirmed that Fontan patients required a lower acenocoumarol dose even when stratified by INR range. 19 Thus, different disease processes for the underlying indications for warfarin use may confound the interpretation of pediatric pharmacogenomics studies involving vitamin K antagonists. This possibility leads to a second important implication: treatment with warfarin was the primary inclusion criterion for the pediatric warfarin studies to ensure adequate cohorts for analysis, not an uncommon situation for any pediatric pharmacogenetic study.…”

“…In the pediatric pharmacogenomics studies discussed above, Fontan patients generally were titrated to a lower target INR range than non‐Fontan patients, and Fontan patients have been reported to require 25% lower doses of warfarin to achieve a comparable target INR compared with non‐Fontan patients with or without congenital heart disease; there are a number of factors related to a single functioning ventricle that may affect warfarin disposition and response, including compromised hepatic blood flow and altered hepatic function . A recently published study of acenocoumarol in Dutch children found the presence of a Fontan circulation to account for 17.3% of the variability in the dose required to achieve the target INR, and confirmed that Fontan patients required a lower acenocoumarol dose even when stratified by INR range . Thus, different disease processes for the underlying indications for warfarin use may confound the interpretation of pediatric pharmacogenomics studies involving vitamin K antagonists.…”

Pharmacogenetics Guidelines: Overview and Comparison of the DPWG, CPIC, CPNDS, and RNPGx Guidelines

“…Pharmacogenetics guidelines of the DPWG, CPIC, CPNDS and RNPGx were found through performing the PubMed search. Supplementary Table S1 presents an overview of the recommendations (Hicks et al, 2015;Hicks et al, 2016;Swen et al, 2011b;Hershfield et al, 2012;Martin et al, 2012;Madadi et al, 2013;Scott et al, 2013;Amstutz et al, 2014;Caudle et al, 2014b;Clancy et al, 2014;Crews et al, 2014;Muir et al, 2014;Ramsey et al, 2014;Relling et al, 2014;Birdwell et al, 2015;Gammal et al, 2015;Shaw et al, 2015;Aminkeng et al, 2016;Lee et al, 2016;Bell et al, 2017;Hicks et al, 2015;Hicks et al, 2016;Johnson et al, 2017;Lamoureux and Duflot, 2017;Moriyama et al, 2017;Quaranta and Thomas, 2017;Woillard et al, 2017;Amstutz et al, 2018;Goetz et al, 2018;Phillips et al, 2018;Maagdenberg et al, 2018;Brown et al, 2019;Desta et al, 2019;Drögemöller et al, 2019;Gonsalves et al, 2019;Relling et al, 2019;Theken et al, 2020;). The DPWG and CPIC guidelines were compared by Bank et al (2018) based on the guidelines published until March 1, 2017.…”

<p>Pharmacogenomic Testing In Pediatrics: Navigating The Ethical, Social, And Legal Challenges</p>

“…The spectrum of potential applications of PGx testing in children ranges from post-transplant5 to pain management6 to psychiatric illness 7–11. Ongoing trials of PGx in pediatric populations continue to gather evidence of clinical utility 12–14. There are a wide range of clinical PGx tests currently available,15 typically including multiple genes (multi-gene panels), though not specific to age group but rather medication class or disease.…”