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

Rodríguez-Fernández, Karine; Reynaldo-Fernández, Gledys; Reyes-González, Stephanie; De Las Barreras, Camila; Rodríguez-Vera, Leyanis; Vlaar, Cornelis; Monbaliu, Jean-Christophe; Stelzer, Torsten; Duconge, Jorge; Mangas-Sanjuan, Victor

doi:10.1016/j.biopha.2023.115977

Article (Scientific journals)

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

Rodríguez-Fernández, Karine; Reynaldo-Fernández, Gledys; Reyes-González, Stephanie et al.

2023 • In Biomedicine and Pharmacotherapy, 170, p. 115977

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/317347

DOI
10.1016/j.biopha.2023.115977

PubMed
38056237

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Keywords :

Warfarin; anticoagulant; CYP2C9 and VKORC1 genotypes; pharmacokinetics; pharmacodynamics; Caribbean Hispanic patients

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 subgroups 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 IC 50 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.

Research Center/Unit :

MolSys - Molecular Systems - ULiège
Center for Integrated Technology and Organic Synthesis
Molecular Sciences Research Center - UPR
Crystallization Design Institute - UPR

Disciplines :

Pharmacy, pharmacology & toxicology

Author, co-author :

Rodríguez-Fernández, Karine; Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Valencia, Spain

Reynaldo-Fernández, Gledys; Institute of Pharmacy and Foods, University of Havana, Havana, Cuba

Reyes-González, Stephanie; Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico -Medical Sciences Campus, San Juan, USA

De Las Barreras, Camila; Institute of Pharmacy and Foods, University of Havana, Havana, Cuba

Rodríguez-Vera, Leyanis; Center for Pharmacometrics and System Pharmacology at Lake Nona (Orlando), Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, USA

Vlaar, Cornelis; Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico -Medical Sciences Campus, San Juan, USA

Monbaliu, Jean-Christophe ; Université de Liège - ULiège > Molecular Systems (MolSys)

Stelzer, Torsten; Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico -Medical Sciences Campus, San Juan, USA ; Molecular Sciences Research Center, Crystallization Design Institute, University of Puerto Rico, San Juan, USA

Duconge, Jorge; Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico -Medical Sciences Campus, San Juan, USA

Mangas-Sanjuan, Victor; Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Valencia, Spain ; Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia-University of Valencia, Valencia, Spain

Language :

English

Title :

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

Publication date :

06 December 2023

Journal title :

Biomedicine and Pharmacotherapy

ISSN :

0753-3322

eISSN :

1950-6007

Publisher :

Elsevier BV

Volume :

170

Pages :

115977

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://api.elsevier.com/content/article/PII:S0753332223017754?httpAccept=text/xml

Funders :

NASA - National Aeronautics and Space Administration

Funding text :

Office of Experimental Program to Stimulate Competitive Research

Available on ORBi :

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