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

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

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dc.contributor.author Rodríguez-Fernández, Karine es_ES
dc.contributor.author Reynaldo-Fernández, G. es_ES
dc.contributor.author Reyes-González, Stephanie es_ES
dc.contributor.author de las Barreras, Camila es_ES
dc.contributor.author Rodríguez-Vera, Leyanis es_ES
dc.contributor.author Vlaar, Cornelis es_ES
dc.contributor.author Monbaliu, Jean-Christophe M. es_ES
dc.contributor.author Stelzer, Torsten es_ES
dc.contributor.author Duconge, Jorge es_ES
dc.contributor.author Mangas-Sanjuan, Victor es_ES
dc.date.accessioned 2024-04-22T18:06:47Z
dc.date.available 2024-04-22T18:06:47Z
dc.date.issued 2024-01 es_ES
dc.identifier.issn 0753-3322 es_ES
dc.identifier.uri http://hdl.handle.net/10251/203670
dc.description.abstract [EN] 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/pharma-codynamic (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. es_ES
dc.description.sponsorship This research was financially sponsored in part by NASA grant #80 NSSC19M0148 from the EPSCoR program, and by grant #1R16 GM149372 from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) . The content of this manuscript does not represent the views of the National Institutes of Health, NASA or the United States Government. No funded writing assistance was utilized in the production of this manuscript. es_ES
dc.language Inglés es_ES
dc.publisher Elsevier es_ES
dc.relation.ispartof Biomedicine & Pharmacotherapy es_ES
dc.rights Reconocimiento - No comercial - Sin obra derivada (by-nc-nd) es_ES
dc.subject Warfarin es_ES
dc.subject Pharmacokinetic/pharmacodynamic es_ES
dc.subject VKORC1 es_ES
dc.subject Hispanic Caribbean es_ES
dc.subject Pharmacodynamic
dc.title New insights into the role of<i> VKORC1</i> polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model es_ES
dc.type Artículo es_ES
dc.identifier.doi 10.1016/j.biopha.2023.115977 es_ES
dc.relation.projectID info:eu-repo/grantAgreement/NASA//80 NSSC19M0148/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/NIGMS//1R16 GM149372/ es_ES
dc.rights.accessRights Abierto es_ES
dc.description.bibliographicCitation Rodríguez-Fernández, K.; Reynaldo-Fernández, G.; Reyes-González, S.; De Las Barreras, C.; Rodríguez-Vera, L.; Vlaar, C.; Monbaliu, JM.... (2024). New insights into the role of<i> VKORC1</i> polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model. Biomedicine & Pharmacotherapy. 170. https://doi.org/10.1016/j.biopha.2023.115977 es_ES
dc.description.accrualMethod S es_ES
dc.relation.publisherversion https://doi.org/10.1016/j.biopha.2023.115977 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion es_ES
dc.description.volume 170 es_ES
dc.identifier.pmid 38056237 es_ES
dc.identifier.pmcid PMC10853672 es_ES
dc.relation.pasarela S\513775 es_ES
dc.contributor.funder National Aeronautics and Space Administration, EEUU es_ES
dc.contributor.funder National Institute of General Medical Sciences, EEUU es_ES


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