Key result
Genetics-based pediatric warfarin dosing achieves ~60% of INRs in therapeutic range by week 2.
Why the study?
No warfarin dosage algorithm based on CYP2C9 and VKORC1 polymorphisms is available for pediatric patients despite extensive adult data.
Can a genetics-based pediatric dosage regimen for warfarin be derived using pharmacometric bridging to optimize INR targets?
Can a genetics-based pediatric dosage regimen for warfarin be derived using pharmacometric bridging to optimize INR targets?
A genetics-based pediatric warfarin dosing algorithm was derived using pharmacometric bridging, potentially improving time in therapeutic range compared to standard dosing.
Pediatric warfarin dosing model may inform initial regimens; extends adult algorithms but leaves open prospective validation of safety and efficacy.
BACKGROUND: Warfarin dosage regimens using CYP2C9 and VKORC1 polymorphisms have been extensively studied in adults and is included in US Food and Drug Administration-approved warfarin labeling. However, no dosage algorithm is available for pediatric patients. OBJECTIVE: To derive a genetics-based pediatric dosge regimen for warfarin, including starting dose and titration scheme. METHODS: A model-based approach was developed based on a previously validated warfarin dosage model in adults, with subsequent comparison to pediatric data from pediatric warfarin dose, genotyping, and international normalized ratio (INR) results. The adult model was based on a previously established model from the CROWN (CReating an Optimal Warfarin dosing Nomogram) trial. Pediatric warfarin data were obtained from a study conducted at the Children's Hospital of Los Angeles with 26 subjects. Variant alleles of CYP2C9 (rs1799853 or *2, and rs1057910 or *3) and the VKORC1 single nucleotide polymorphism (SNP) rs9923231 (-1639 G>A) were assessed, where the rs numbers are reference SNP identification tags assigned by the National Center for Biotechnology Information. RESULTS: A pediatric warfarin model was derived using the previously validated model and clinical pharmacology considerations. The model was validated, and clinical trial simulation and stochastic modeling were used to optimize pediatric dosage and titration. The final dosage regimen was optimized based on simulations targeting a high (≥60%) proportion of INRs within the therapeutic range by week 2 of warfarin therapy while minimizing INRs >3.5 or <2. CONCLUSIONS: The proposed pediatric warfarin dosage scheme based on individual CYP2C9 (alleles *1,*2,*3) and VKORC1 rs9923231 (-1639 G>A) genotypes may offer improved dosage compared to current treatment strategies, especially in patients with variant CYP2C9 and VKORC1 alleles. This pilot study provides the foundation for a larger prospective evaluation of genetics-based warfarin dosage in pediatric patients.
No takes yet. Share an insight, caveat, or question.
Lala et al. (2013) studied Pediatric patients requiring warfarin (n=26). Genetics-based pediatric warfarin dosage regimen vs. Current treatment strategies was evaluated on Proportion of INRs within the therapeutic range by week 2 of warfarin therapy. A genetics-based pediatric warfarin dosage scheme was derived using pharmacometric bridging, optimized to target ≥60% of INRs within the therapeutic range by week 2.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: