New insights into the role of VKORC1 polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model

VKORC1型 华法林 加药 CYP2C9 药效学 非金属 医学 人口 药理学 药代动力学 抗凝剂 药物遗传学 内科学 基因型 生物 遗传学 环境卫生 细胞色素P450 新陈代谢 心房颤动 基因
作者
Karine Rodríguez-Fernández,Gledys Reynaldo Fernández,Stephanie Reyes-González,Camila de las Barreras,Leyanis Rodríguez-Vera,Cornelis P. Vlaar,Jean‐Christophe M. Monbaliu,Torsten Stelzer,Jorge Duconge,Víctor Mangas‐Sanjuán
出处
期刊:Biomedicine & Pharmacotherapy [Elsevier BV]
卷期号:170: 115977-115977
标识
DOI:10.1016/j.biopha.2023.115977
摘要

Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients. INR, and CYP2C9 and VKORC1 genotypes from 138 patients were used to develop a population PK/PD model in NONMEM. The structural definition of a previously published PD model for INR was implemented. A numerical evaluation of the parameter-covariate relationship was performed. Simulations were conducted to determine optimal dosing strategies for each genotype combinations, focusing on achieving therapeutic INR levels. Findings revealed elevated IC50 for G/G, G/A, and A/A VKORC1 haplotypes (11.76, 10.49, and 9.22 mg/L, respectively), in this population compared to previous reports. The model-guided dosing analysis recommended daily warfarin doses of 3-5 mg for most genotypes to maintain desired INR levels, although subjects with combination of CYP2C9 and VKORC1 genotypes * 2/* 2-, * 2/* 3- and * 2/* 5-A/A would require only 1 mg daily. This research underscores the potential of population PK/PD modeling to inform personalized warfarin dosing in populations typically underrepresented in clinical studies, potentially leading to improved treatment outcomes and patient safety. By integrating genetic factors and clinical data, this approach could pave the way for more effective and tailored anticoagulation therapy in diverse patient groups.

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