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Published on: January 19, 2024
Genetics-based pediatric warfarin dosage regimen derived using pharmacometric bridging.
Mallika Lala1, Gilbert J Burckart, Cheryl M Takao
1Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland ; School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia.
Summary
A new warfarin dosing regimen for children was developed using genetic information. This genetics-based approach aims to improve warfarin dosing accuracy and therapeutic outcomes in pediatric patients.
Area of Science:
- Pharmacogenomics
- Pediatric pharmacology
- Drug dosing optimization
Background:
- Warfarin dosing in adults is guided by CYP2C9 and VKORC1 genetic polymorphisms, as recognized by the FDA.
- No established genetic-based dosing algorithm currently exists for pediatric patients.
Purpose of the Study:
- To develop a genetics-based warfarin dosing regimen for pediatric patients.
- The regimen includes both an initial starting dose and a titration scheme.
Main Methods:
- A model-based approach adapted from an established adult warfarin dosage model.
- Pediatric data from 26 subjects at Children's Hospital of Los Angeles were used for comparison.
- Genotyping focused on CYP2C9 variant alleles (*2, *3) and the VKORC1 rs9923231 SNP.
Main Results:
- A validated pediatric warfarin dosage model was derived.
- Simulations and stochastic modeling optimized the pediatric dosage and titration strategy.
- The optimized regimen targets a high proportion of international normalized ratios (INRs) within the therapeutic range by week 2.
Conclusions:
- The proposed genetics-based warfarin dosage scheme, considering CYP2C9 and VKORC1 genotypes, may enhance pediatric dosing.
- This pilot study lays the groundwork for future prospective evaluations of genetic-guided warfarin therapy in children.
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