A New Pharmacogenetic Algorithm to Predict the Most Appropriate Dosage of Acenocoumarol for Stable Anticoagulation in a Mixed Spanish Population

Abstract

There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (<11 mg/week, 11–21 mg/week, >21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in extreme-dosage patients. The predictability of the pharmacogenetic algorithm did not vary significantly between diseases.

Pharmacogenetic Variation in Over 100 Genes in Patients Receiving Acenocumarol

“…Our model is similar to others in that it includes typical clinical variants (age, sex, weight, and height), a dose prediction around 50% confidence, and the inclusion of VKORC1 as the primary determinant of acenocumarol dose. And even though we report VKORC1 rs9934438 vs. VKORC1 9923231 this latter, most commonly studied (Zhang et al, 2015 ; Tong et al, 2016 ) these are in complete LD. Finally, dose assessment using this model closely approached the dose received to achieve an INR 2–3, except for patient R4.…”

“…We investigated coding, 25 bp of adjacent introns, and 5′ and 3′ UTR regions of 110 genes related to general pharmacogenomics including core pharmacokinetics and pharmacodynamics targets in 100 DNA samples. We selected these genes according to the general PGx and the PK/PD of acenocumarol by searching the available literature using the keywords, pharmacogenetics, pharmacogenomics, acenocumarol, coumarin pharmacokinetics, and pharmacodynamics (van Leeuwen et al, 2008 ; Soria et al, 2009 ; Whirl-Carrillo et al, 2012 ; Tong et al, 2016 ). Regions of interest were captured using a Haloplex custom Target Enrichment System (Agilent Technologies, Santa Clara, CA, USA) defined for 150 × 2 paired-end reads, in a panel size of 1.1Mbp.…”

“…Endeavors are currently ongoing to amass a more comprehensive picture of the pharmacogenetic variation in Mexican Mestizos. Here, we investigated genetic variation in over 100 genes by targeted NGS in patients receiving acenocumarol, including genes involved in general pharmacokinetics and pharmacodynamics, vitamin K recycling, and coagulation proteins, these latter also potentially affecting acenocumarol response (Allan et al, 2005 ; Harrington et al, 2008 ; Carcao et al, 2015 ; Tong et al, 2016 ). Clinical and genetic data were used to develop an algorithm to explain dose variability in this group of patients.…”

Clinical Implementation of Pharmacogenetic Testing in a Hospital of the Spanish National Health System: Strategy and Experience Over 3 Years

“…Another key point for the implementation of pharmacogenetics in our hospital was bringing together research and clinical practice by promoting collaborative investigation and decision making; several investigation projects are underway evaluating the clinical results of this implementation. This approach led to a direct impact on clinical practice and a more active interaction with other medical specialties through lectures and clinical meetings, allowing the creation of more efficient and optimized treatment guidelines and protocols, as shown in the physician survey performed.…”

Pharmacogenetic studies with oral anticoagulants. Genome-wide association studies in vitamin K antagonist and direct oral anticoagulants

“…Different acenocoumarol pharmacogenetic-guided dosing algorithms have been derived in different cohorts from different populations [ 17 , 59 – 67 ]. An observational retrospective study analyzed 8 different acenocoumarol pharmacogenetic algorithms in a cohort of 189 patients [ 65 ].…”