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

Toshinori Hirai, Takahiko Aoyama, Yasuhiro Tsuji, Toshimasa Itoh, Yoshiaki Matsumoto, Takuya Iwamoto

British journal of clinical pharmacology 2024 Mar

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Genotype-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. Using 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. A 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. Model-informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment. © 2023 British Pharmacological Society.

Citation

Toshinori Hirai, Takahiko Aoyama, Yasuhiro Tsuji, Toshimasa Itoh, Yoshiaki Matsumoto, Takuya Iwamoto. Kinetic-pharmacodynamic model of warfarin for prothrombin time-international normalized ratio in Japanese patients. British journal of clinical pharmacology. 2024 Mar;90(3):828-836