Kinetic–pharmacodynamic model of warfarin for prothrombin time–international normalized ratio in Japanese patients

Abstract

AimsGenotype‐guided dosing algorithms can explain about half of the interindividual variability in prothrombin time–international normalized ratio (PT‐INR) under warfarin treatment. This study aimed to refine a published kinetic–pharmacodynamic model and guide warfarin dosage for an optimal PT‐INR based on renal function.MethodsUsing a retrospective cohort of adult patients (>20 years) who were administered warfarin and underwent PT‐INR measurements, we refined the kinetic–pharmacodynamic model with age and the genotypes of cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 using the PRIOR subroutine in the nonlinear‐mixed‐effect modelling programme. We searched the significant covariates for parameters, such as the dose rate for 50% inhibition of coagulation (EDR50), using a stepwise forward and backward method. Monte Carlo simulation determined a required daily dose of warfarin with a target range of PT‐INR (2.0–3.0 or 1.6–2.6) based on the significant covariates.ResultsA total of 350 patients with 2762 PT‐INR measurements were enrolled (estimated glomerular filtration rate [eGFR]: 47.5 [range: 2.6–199.0] mL/min/1.73 m2). The final kinetic–pharmacodynamic model showed that the EDR50 changed power functionally with body surface area, serum albumin level and eGFR. Monte Carlo simulation revealed that a lower daily dose of warfarin was required to attain the target PT‐INR range as eGFR decreased.ConclusionsModel‐informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment.