Genetics-based pediatric warfarin dosage regimen derived using pharmacometric bridging.
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.
Office 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.
Mallika
M
Lala
Gilbert J
GJ
Burckart
Cheryl M
CM
Takao
Vera
V
Pravica
Jeremiah D
JD
Momper
Jogarao V S
JV
Gobburu
CYP2C9; VKORC1; pediatrics; pharmacogenetics; warfarin