Kinetic-pharmacodynamic model of warfarin for prothrombin time-international normalized ratio in Japanese patients
© 2023 British Pharmacological Society..
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 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.
CONCLUSIONS: Model-informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:90 |
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| Enthalten in: |
British journal of clinical pharmacology - 90(2024), 3 vom: 30. März, Seite 828-836 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hirai, Toshinori [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.02.2024 Date Revised 05.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bcp.15967 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Hirai, Toshinori |e verfasserin |4 aut | |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 British Pharmacological Society. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 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 | ||
| 520 | |a CONCLUSIONS: Model-informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a model-informed precision dosing | |
| 650 | 4 | |a pharmacometrics | |
| 650 | 4 | |a prothrombin time-international normalized ratio | |
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| 650 | 4 | |a warfarin | |
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| 700 | 1 | |a Aoyama, Takahiko |e verfasserin |4 aut | |
| 700 | 1 | |a Tsuji, Yasuhiro |e verfasserin |4 aut | |
| 700 | 1 | |a Itoh, Toshimasa |e verfasserin |4 aut | |
| 700 | 1 | |a Matsumoto, Yoshiaki |e verfasserin |4 aut | |
| 700 | 1 | |a Iwamoto, Takuya |e verfasserin |4 aut | |
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