Relationship between warfarin dosage and international normalized ratio: a dose-response analysis and evaluation...

Area of Science:

• Pharmacology
• Pharmacogenetics
• Clinical Pharmacy

Background:

• Warfarin dosing requires careful management to maintain therapeutic international normalized ratio (INR) levels.
• Individual variability in warfarin response necessitates personalized dosing strategies.
• Existing models may not fully capture the complex interplay of factors influencing warfarin efficacy.

Purpose of the Study:

• To develop a robust dose-response model for warfarin therapy.
• To establish the relationship between daily warfarin dose and INR.
• To validate the model's stability and reliability using external clinical data.

Main Methods:

• Utilized NONMEM software and the Michaelis-Menten equation to model warfarin dose-INR relationship.
• Analyzed clinical data from 676 outpatients, including demographics, medications, and CYP2C9/VKORC1 genotypes.
• Assessed model performance using goodness-of-fit plots, bootstrap resampling, and external validation datasets.

Main Results:

• The developed model demonstrated superior pharmacological expressiveness compared to multivariate linear regression.
• Key parameters Km (3.56 mg) and Hill coefficient (0.512) were determined, with significant individual variability.
• Identified genetic factors (CYP2C9, VKORC1), amiodarone, and non-valve replacement surgery as significant modulators of warfarin Km.
• Age and fat-free mass (FFM) influenced Km, and the model achieved a 73.0% prediction accuracy within ±20% error on external data.

Conclusions:

• A reliable warfarin dose-response model was successfully established.
• The model confirmed expected genotype and demographic influences on warfarin pharmacokinetics.
• This individualized warfarin therapy model shows promise for Chinese outpatient populations.