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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 (EDR 50 ), 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 EDR 50 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.

Titel:	Kinetic-pharmacodynamic model of warfarin for prothrombin time-international normalized ratio in Japanese patients.
Autor/in / Beteiligte Person:	Hirai, T ; Aoyama, T ; Tsuji, Y ; Itoh, T ; Matsumoto, Y ; Iwamoto, T
Link:	Zum Volltext
Zeitschrift:	British journal of clinical pharmacology, Jg. 90 (2024-03-01), Heft 3, S. 828-836
Veröffentlichung:	Oxford : Wiley-Blackwell ; <i>Original Publication</i>: London, Macmillan Journals Ltd., 2024
Medientyp:	academicJournal
ISSN:	1365-2125 (electronic)
DOI:	10.1111/bcp.15967
Schlagwort:	Adult Humans Cytochrome P-450 CYP2C9 genetics Genotype International Normalized Ratio Japan Prothrombin Prothrombin Time Retrospective Studies Vitamin K Epoxide Reductases genetics Anticoagulants pharmacokinetics Warfarin pharmacokinetics
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Kinetic-pharmacodynamic model of warfarin for prothrombin time-international normalized ratio in Japanese patients.