Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and adverse effects

Abstract

Warfarin is used in paediatric populations, but dosing algorithms incorporating pharmacogenetic data have not been developed for children. Previous studies have produced estimates of the effect of polymorphisms in CYP2C9 and VKORC1 on stable warfarin dosing, but data on time in therapeutic range, initial dosing and adverse effects are limited. Participants (n=97) were recruited, and routine clinical data and salivary DNA samples were collected from all participants, and analysed for CYP2C9*2, *3 and VKORC1-1639 polymorphisms.VKORC1 -1639 was associated with a greater proportion of the first six months’ treatment time spent within the target INR range, accounting for an additional 9.5% of the variance in the proportion of time. CYP2C9*2 was associated with a greater likelihood of INR values exceeding the target range during the initiation of treatment (OR [per additional copy] 4.18, 95% CI 1.42, 12.34). CYP2C9*2 and VKORC1-1639 were associated with a lower dose requirement, and accounted for almost 12% of the variance in stable dose. VKORC1-1639 was associated with an increased likelihood of mild bleeding complications (OR [heterozygotes vs homozygotes] 4.53, 95% CI 1.59, 12.93). These data show novel associations between VKORC1-1639 and CYP2C9*2 and INR values in children taking warfarin, as well as replicating previous findings with regard to stable dose requirements. The development of pharmacogenomic dosing algorithms for children using warfarin has the potential to improve clinical care in this population.

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.…”

“…For example, in the first pediatric study, age accounted for 28.3% of dose variability, and genetic factors contributed ~4% (3.7% for VKORC1 and 0.4% for CYP2C9). In six subsequent studies, the genetic contribution (predominantly VKORC1 genotype) was much larger, accounting for 11.9–52% of dose variability, but in four of these the contribution of age, height, and weight as surrogates for the “developmental” component (29.2–52.8% of dose variability) exceeded the genetic contribution (11.9–21.1%) . Noteworthy are the various ways that “dose” was expressed in the statistical analyses: uncorrected (mg), corrected for weight (mg/kg) or transformed for normalization (mg1/2, (mg/kg)1/2, and log(mg/kg)).…”

“…In six subsequent studies, the genetic contribution (predominantly VKORC1 genotype) was much larger, accounting for 11.9-52% of dose variability, but in four of these the contribution of age, height, and weight as surrogates for the "developmental" component (29.2-52.8% of dose variability) exceeded the genetic contribution (11.9-21.1%). 11,15,17,18 Noteworthy are the various ways that "dose" was expressed in the statistical analyses: uncorrected (mg 15,18 ), corrected for weight (mg/kg 16 ) or transformed for normalization (mg1/2, 11,12 (mg/kg)1/2, 22 and log(mg/kg) 17 ). Equally inconsistent is the choice of "developmental" factor given that changes in age, height, and weight tend to be quite wellcorrelated during growth and development.…”

Anticoagulant prophylaxis and therapy in children: current challenges and emerging issues

“… investigated the possible impact of patient deconditioning and vitamin K intake or fasting upon the INR response to warfarin. Since 2010, 13 original studies and two meta‐analyses focused on warfarin pharmacogenomics have been published, and these were identified with this search strategy. Data synthesis of these studies confirms that the identified vitamin K epoxide reductase complex subunit 1 ( VKORC1 ) and cytochrome P450 2CP ( CYP2CP ) variants probably contribute to a reduction in warfarin dosing requirements as compared with wild‐type alleles; however, all studies were conducted in patients with warfarin steady states, and most studies had small cohorts with limited ethnic diversity.…”

Pharmacogenetic Markers of Drug Efficacy and Toxicity

“…While warfarin treatment accounts for 10% of all adverse drug reaction (ADR) admissions in adults in the UK, in pediatrics it is a very uncommon cause of ADRs. 13 There have been seven pharmacogenetic studies of warfarin in children [14][15][16][17][18][19][20] (Table 1). Due to the heterogeneity in the data reported in studies, a meta-analysis would be difficult to undertake, unless individual patient data were available.…”