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

被引：1

作者：

Hirai, Toshinori ^{[1
]}

Aoyama, Takahiko ^{[2
]}

Tsuji, Yasuhiro ^{[2
]}

Itoh, Toshimasa ^{[3
]}

Matsumoto, Yoshiaki ^{[2
]}

Iwamoto, Takuya ^{[1
]}

机构：

[1] Mie Univ, Mie Univ Hosp, Fac Med, Dept Pharm, 2-174 Edobashi, Tsu, Mie 5148507, Japan

[2] Nihon Univ, Sch Pharm, Lab Clin Pharmacometr, Funabashi, Chiba, Japan

[3] Tokyo Womens Med Univ, Med Ctr East, Dept Pharm, Tokyo, Japan

来源：

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY | 2024年 / 90卷 / 03期

基金：

日本学术振兴会;

关键词：

model-informed precision dosing; pharmacometrics; prothrombin time-international normalized ratio; renal function; warfarin; CHRONIC KIDNEY-DISEASE; ATRIAL-FIBRILLATION; PROTEIN-BINDING; CYP2C9; THERAPY; RISK; ANTICOAGULATION; POLYMORPHISMS; HEMORRHAGE; OUTCOMES;

D O I：

10.1111/bcp.15967

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Aims: 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.Methods: 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.Results: 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 m(2)). 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.Conclusions: Model-informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment.

引用

页码：828 / 836

页数：9

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