Acenocoumarol Dose Research Articles

A novel acenocoumarol pharmacogenomic dosing algorithm for the Greek population of EU-PACT trial.

To generate and validate a pharmacogenomic-guided (PG) dosing algorithm for acenocoumarol in the Greek population. To compare its performance with other PG algorithms developed for the Greek population. A total of 140 Greek patients participants of the EU-PACT trial for acenocoumarol, a randomized clinical trial that prospectively compared the effect of a PG dosing algorithm with a clinical dosing algorithm on the percentage of time within INR therapeutic range, who reached acenocoumarol stable dose were included in the study. CYP2C9 and VKORC1 genotypes, age and weight affected acenocoumarol dose and predicted 53.9% of its variability. EU-PACT PG algorithm overestimated acenocoumarol dose across all different CYP2C9/VKORC1 functional phenotype bins (predicted dose vs stable dose in normal responders 2.31 vs 2.00 mg/day, p = 0.028, in sensitive responders 1.72 vs 1.50 mg/day, p = 0.003, in highly sensitive responders 1.39 vs 1.00 mg/day, p = 0.029). The PG algorithm previously developed for the Greek population overestimated the dose in normal responders (2.51 vs 2.00 mg/day, p < 0.001). Ethnic-specific dosing algorithm is suggested for better prediction of acenocoumarol dosage requirements in patients of Greek origin.

Protective Effect of Pretreatment with Acenocoumarol in Cerulein-Induced Acute Pancreatitis.

Coagulation is recognized as a key player in inflammatory and autoimmune diseases. The aim of the current research was to examine the effect of pretreatment with acenocoumarol on the development of acute pancreatitis (AP) evoked by cerulein. Methods: AP was induced in rats by cerulein administered intraperitoneally. Acenocoumarol (50, 100 or 150 µg/kg/dose/day) or saline were given once daily for seven days before AP induction. Results: In rats with AP, pretreatment with acenocoumarol administered at the dose of 50 or 100 µg/kg/dose/day improved pancreatic histology, reducing the degree of edema and inflammatory infiltration, and vacuolization of acinar cells. Moreover, pretreatment with acenocoumarol given at the dose of 50 or 100 µg/kg/dose/day reduced the AP-evoked increase in pancreatic weight, serum activity of amylase and lipase, and serum concentration of pro-inflammatory interleukin-1β, as well as ameliorated pancreatic DNA synthesis and pancreatic blood flow. In contrast, acenocoumarol given at the dose of 150 μg/kg/dose did not exhibit any protective effect against cerulein-induced pancreatitis. Conclusion: Low doses of acenocoumarol, given before induction of AP by cerulein, inhibit the development of that inflammation.

The impact of CYP4F2, ABCB1, and GGCX polymorphisms on bleeding episodes associated with acenocoumarol in Russian patients with atrial fibrillation.

Oral anticoagulants are commonly used to treat patients with thromboembolic pathology. Genetic variations could influence personal response to anticoagulant drugs. Acenocoumarol (AC) is a vitamin K antagonist used in anticoagulant therapy and as a prophylaxis measure in Europe. In this study, we assessed the effect of CYP4F2 rs2108622, ABCB1, and GGCX polymorphisms on the safety profile and regime dosing of AC in patients with nonvalvular atrial fibrillation. Fifty patients aged 40-70 years were included. All patients received AC in the dose of 1-6 mg daily with a target international normalized ratio of 2.0-3.0. Genotyping for polymorphism markers C3435T for the ABCB1 gene, rs2108622 for the CYP4F2 gene, and rs11676382 for the GGCX gene were designed using polymerase chain reaction and restriction fragment length polymorphism. Statistical analysis was performed using the Fisher exact test and the Mann-Whitney U test. We found that CYP4F2 rs2108622 CT carriers required a higher AC dose than CC (p=0.0366), and CT and TT carriers required a higher AC dose than CC (p=0.0314). We found that ABCB1 CT and TT genotypes are associated with a higher risk of bleeding. No influence of ABCB1 and GGCX polymorphisms on the doses of AC was established. CYP4F2 could still be a genetic factor responsible for the personal variability of AC metabolism.

Influence of VKORC1 and CYP2C9 Polymorphisms on Daily Acenocoumarol Dose Requirement in South Indian Patients With Mechanical Heart Valves.

Chronic rheumatic heart disease (RHD) patients who undergo valve replacement with mechanical valves require lifelong anticoagulation. Acenocoumarol, a vitamin K antagonist has a narrow therapeutic range and wide inter-individual variability. Our aim was to investigate the influence of polymorphisms of VKORC1 and CYP2C9 genes on the mean daily dose requirement of acenocoumarol. 205 chronic RHD patients, with mechanical heart valves and on acenocoumarol therapy, were recruited. Genotyping for VKORC1 (-1639G>A and 1173C>T) and CYP2C9 (*2 & *3 alleles) polymorphisms was done by PCR-RFLP. There was complete linkage disequilibrium between VKORC1 polymorphisms (r2 = 0.98, D' = 1.0, LOD = 74.02). VKORC1 genotype distribution for GG/CC, GA/CT, and AA/TT were 57.6%, 36.1%, and 6.3%, respectively. CYP2C9 genotype distribution for *1/*1, *1/*3, *1/*2, *2/*2, and *2/*3 were 78.5%, 14.1%, 6.3%, 0.5%, and 0.5%, respectively. Patients with a wild type of both VKORC1 (-1639GG and 1173CC) and CYP2C9 gene variants required higher acenocoumarol dose compared to those with mutant genotype ( P = 0.023 and P = 0.008 respectively). On combined genotype analysis, patients having a combination of wild type of VKORC1 with wild type of CYP2C9 (44.4%) required higher daily dose compared to patients bearing heterozygous VKORC1 (-1639GA & 1173CT) with wild type of CYP2C9 (30.2%, P = 0.008). Presence of a mutant allele of VKORC1 (-1639A & 1173T) and CYP2C9 genes increased the odds of requiring a lower mean dosage of acenocoumarol. Studying the combination of genotypes in RHD patients could predict acenocoumarol dose requirement more accurately.

Healing effect of low doses of acenocoumarol in the course of ischemia/reperfusion-induced acute pancreatitis in rats

Healing effect of low doses of acenocoumarol in the course of ischemia/reperfusion-induced acute pancreatitis in rats

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

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.

ABCB1 polymorphism and acenocoumarol safety in patients with valvular atrial fibrillation.

Oral anticoagulant drugs (AD) are commonly used to treat patients with thromboembolic diseases. The ADs have narrow therapeutic index and wide pharmacokinetic and pharmacodynamic interindividual variability. Some genetic variations could influence interindividual variability in response to AD. Acenocoumarol (AC) is a coumarin, vitamin K derivate with antagonistic activity, used as anticoagulant therapy mainly in Central Europe and Latin America. P - glycoprotein (PGP), a transporter encoded by the ABCB1 gene, plays a major role in the drug disposition [1]. PGP is expressed in normal tissues, where it performs a defensive role against potentially toxic substances in intestinal cells and endothelial cells of the brain capillary endothelium. ABCB1 - is highly polymorphic, C3435T polymorphism in exon 26 has been associated with the expression of PGP [2]. There is some evidence that PGP could influence coumarin sensitivity. To assess effects of the ABCB1 pilymorphisms on safety profile and dosing regimen of acenocoumarol in the patients with valvular atrial fibrillation. 50 patients (34 male and 16 female), 40-70 years of age were included. All patients received acenocoumarol at doses of 1-6 mg daily with a target international normalized ratio (INR) of 2.0 to 3.0. Genotyping for polymorphism marker C3435T of ABCB1 gen was performed using PCR and RFLP (restriction fragment length polymorphisms) techniques. Statistics were performed by Fishers exact tests. All enrolled patients provided written informed consent. Genotype CC was found in 10 patients (20%), genotype CT in 25 patients (50%) and genotype TT in 15 patients (30%). In the CC group (n = 10) bleeding was found in 1 patient (2%). There were 19 patients (38%) with bleedings in combined group of CT and TT genotype (p = 0.0366). We compared the average doses of acenocoumarol in groups identified according to their genotypes: CC (3.45 mg/day), CT (2.64 mg/day), TT (3.07 mg/day) and found no significant differences. ABCB1 CT and TT genotypes were found to be significantly associated with higher risk of bleeding. There was no influence of ABCB1 polymorphisms on dosing regimens of acenocoumarol.

Estimation and validation of acenocoumarol dosing algorithms in Bulgarian patients with cardiovascular diseases.

It was found that VKORC-1639G>A (25.5%), CYP2C9*2 (7.8%), CYP2C9*3 (6.1%), age (13.6%) and diagnosis (6.0%) significantly affected acenocoumarol dose variability in the derivation cohort. These factors with additional factors, such as sex (0.1%, p = 0.76), weight (2.6%, p = 0.14) and amiodarone use (3.0%, p = 0.059) accounted for 46.5% and 23.0% of the dose variability for genetic and clinical models, respectively. Based on the results of this investigation, validated clinical and pharmacogenetic algorithms for the prediction of a stable anticoagulant dose were developed, specifically designed for the Bulgarian population.

Genotype-based dosage of acenocoumarol in highly-sensitive geriatric patients.

Our aim was to determinate the acenocoumarol dose requirement in highly sensitive geriatric patients, based on a minimum of genotype (VKORC1 and CYP2C9) data. We used a Gaussian kernel density estimation test to identify patients highly sensitive to the drug and PHARMACHIP®-Cuma test (Progenika Biopharma, SA, Grifols, Spain) to determine the CYP2C9 and VKORC1 genotype. All highly sensitive geriatric patients were taking ≤5.6 mg/week of acenocoumarol (AC), and 86% of these patients presented the following genotypes: CYP2C9*1/*3 or CYP2C9*1/*2 plus VKORC1 A/G, CYP2C9*3/*3, or VKORC1 A/A. VKORC1 A and CYP2C9*2 and/or *3 allelic variants extremely influence on AC dose requirement of highly sensitive geriatric patients. These patients display acenocoumarol dose requirement of ≤5.6 mg/week.

High prevalence of VKORC1*3 (G9041A) genetic polymorphism in north Indians: A study on patients with cardiac disorders on acenocoumarol.

Coumarin derivatives such as warfarin and acenocoumarol are used in various disorders such as deep venous thrombosis, pulmonary embolism, atrial fibrillation and artificial heart valves. They have improved prognosis of patients with thromboembolic disease. An individual's response to coumarins depends on several factors. The non-genetic factors include age, gender, body mass index, diet and interacting drugs. Among the genetic factors, the cytochrome P450 system and vitamin K epoxide reductase complex subunit 1 play a key role in drug metabolism. This was a prospective hospital based study in which allele and genotypic frequencies of CYP2C9 gene polymorphisms; 430C>T and 1075A>C and VKORC1 gene polymorphisms; 1639G>A, 9041G>A and 6009C>T in 106 alleles of north Indian patients with valve replacement on acenocoumarol were determined and their effect on acenocoumarol dosing was studied. To the best of our knowledge, this is first report of VKORC1 9041G>A and 6009C>T gene polymorphisms and their effect on acenocoumarol dosing from north India. In 53 patients with valve replacement on acenocoumarol with stable INR, the allele frequency of CYP2C9*2 and CYP2C9*3 gene polymorphisms was 0.05 and 0.17 respectively and that of VKORC1 *2,*3 and *4 gene polymorphisms was 0.15, 0.72 and 0.11 respectively. The presence of CYP2C9*3 or VKORC1*2 gene polymorphism were associated with decrease in acenocoumarol dose requirements (p values 0.03 and 0.02 respectively).This study confirmed the association of lower mean weekly dosages of acenocoumarol in patients with CYP2C9*3 and VKORC1*2 gene polymorphisms. An unusually high frequency of 9041A polymorphism in VKORC1 was found in study population.

P-glycoprotein: a clue to vitamin K antagonist stabilization.

Acenocoumarol is a vitamin K antagonist used in some European countries. As warfarin, this drug is characterized by a narrow therapeutic index and a large interindividual variability. The objective of this study was to assess the involvement of ABCB1 polymorphisms on acenocoumarol treatment. An observational cohort study was conducted to assess whether there is an association between the presence of the allelic variants of the ABCB1 gene coding for P-glycoprotein and acenocoumarol stabilization and daily doses during the first 35 days of treatment. One hundred and fifteen patients met the inclusion criteria. The results of the clinical study showed that carriers of ABCB1 c.3435TT were more rapidly stabilized than wild-type patients (HR: 2.97, 95% CI: 1.23-7.18; p = 0.02). The same tendency was observed for the ABCB1 c.2677GT and 2677TT genotypes compared with ABCB1 c.2677GG. The ABCB1 c.2677TT genotype was also associated with a significant increase in doses of acenocoumarol (p = 0.03), the same tendency was observed with the ABCB1 c.3435TT genotype compared with the wild-type patients. These data suggest that ABCB1 polymorphisms could be involved in the response to acenocoumarol treatment.

Point-of-care testing and INR within-subject variation in patients receiving a constant dose of vitamin K antagonist.

Many patients treated with vitamin K antagonists (VKA) determine their INR using point-of-care (POC) whole blood coagulation monitors. The primary aim of the present study was to assess the INR within-subject variation in self-testing patients receiving a constant dose of VKA. The second aim of the study was to derive INR imprecision goals for whole blood coagulation monitors. Analytical performance goals for INR measurement can be derived from the average biological within-subject variation. Fifty-six Thrombosis Centres in the Netherlands were invited to select self-testing patients who were receiving a constant dose of either acenocoumarol or phenprocoumon for at least six consecutive INR measurements. In each patient, the coefficient of variation (CV) of INRs was calculated. One Thrombosis Centre selected regular patients being monitored with a POC device by professional staff. Sixteen Dutch Thrombosis Centres provided results for 322 selected patients, all using the CoaguChek XS. The median within-subject CV in patients receiving acenocoumarol (10.2 %) was significantly higher than the median CV in patients receiving phenprocoumon (8.6 %) (p = 0.001). The median CV in low-target intensity acenocoumarol self-testing patients (10.4 %) was similar to the median CV in regular patients monitored by professional staff (10.2 %). Desirable INR analytical imprecision goals for POC monitoring with CoaguChek XS in patients receiving either low-target intensity acenocoumarol or phenprocoumon were 5.1 % and 4.3 %, respectively. The approximate average value for the imprecision of the CoaguChek XS, i. e. 4 %, is in agreement with these goals.

An acenocoumarol dosing algorithm exploiting clinical and genetic factors in South Indian (Dravidian) population

The objective of this study was to determine the influence of CYP2C9, VKORC1, CYP4F2, and GGCX genetic polymorphisms on mean daily dose of acenocoumarol in South Indian patients and to develop a new pharmacogenetic algorithm based on clinical and genetic factors. Patients receiving acenocoumarol maintenance therapy (n = 230) were included in the study. Single nucleotide polymorphisms (SNP) of CYP2C9, VKORC1, CYP4F2, and GGCX were genotyped by real-time polymerase chain reaction (RT-PCR) method. The mean daily acenocoumarol maintenance dose was found to be 3.7 ± 2.3 (SD) mg/day. The CYP2C9 *1*2, CYP2C9 *1*3, and CYP2C9 *2*3 variant genotypes significantly reduced the dose by 56.7 % (2.0 mg), 67.6 % (1.6 mg), and 70.3 % (1.5 mg) than wild-type carriers 4.1 mg, p < 0.0001. The genetic variants of CYP2C9 and GGCX (rs11676382) were found to be associated with lower acenocoumarol dose, whereas CYP4F2 (rs2108622) was associated with higher doses. Age, body mass index (BMI), variation of CYP2C9, VKORC1, CYP4F2, and GGCX were the major determinants of acenocoumarol maintenance dose, accounting for 61.8 % of its variability (adjusted r (2) = 0.615, p < 0.0001). Among the VKORC1 variants, rs9923231 alone contributed up to 28.6 % of the acenocoumarol dose variation. VKORC1 rs9923231 polymorphism had the highest impact on acenocoumarol daily dose. A new pharmacogenetic algorithm was established to determine the acenocoumarol dose in South Indian population.

Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm.

To develop an acenocoumarol (ACN) dosing algorithm for patients with atrial fibrillation or venous thromboembolism, considering the influence on the stable ACN dose of clinical factors and gene polymorphisms, including CYP2C9*2/*3, VKORC1, CYP4F2*3, ABCB1, APOE, CYP2C19*2/*17, and GGCX. A retrospective observational study was carried out to obtain clinical and pharmacogenetic dose algorithms by multiple linear regression of results in a cohort of 134 patients under treatment with a stable ACN dose for atrial fibrillation or venous thromboembolism and to test them in an independent validation cohort of 30 patients.The pharmacogenetic dosing algorithm included CYP2C9, VKORC1, and APOE, which explained 56.6% of the variability in the stable ACN dose. Lower deviation from the stable dose and increased accuracy were shown by the pharmacogenetic algorithm, which correctly classified 67% of patients with a deviation of up to 20%. The variability in the stable ACN dose was better explained by a pharmacogenetic algorithm including clinical and genetic factors (CYP2C9, VKORC1, and APOE) than by a clinical algorithm, providing a more accurate dosage prediction.

Genetic determinants of acenocoumarol and warfarin maintenance dose requirements in Slavic population: A potential role of CYP4F2 and GGCX polymorphisms

IntroductionVKORC1 and cytochrome CYP2C9 genetic variants contribute largely to inter-individual variations in vitamin K antagonists (VKAs) dose requirements. Cytochrome P450 4F2 isoform (CYP4F2), gamma-glutamyl carboxylase (GGCX) and apolipoprotein E (APOE) polymorphisms have been suggested to be of minor significance. Materials and MethodsWe sought to assess the impact of those polymorphisms on dose requirements in Central-Eastern European cohort of 479 patients receiving acenocoumarol (n=260) or warfarin (n=219). ResultsThere were no differences between the acenocoumarol and warfarin groups with regard to the gender, age, body mass index and international normalized ratio. The VKORC1 c.-1639A allele carriers required a lower dose of acenocoumarol and warfarin than the non-carriers (28.0 [21.0–35.0] vs. 42.0 [28.0–56.0] mg/week, p<0.0001; 35.0 [28.0–52.0] vs. 52.0 [35.0–70.0] mg/week, p=0.0001, respectively). Carriers of *2 and/or *3 variant alleles for CYP2C9 also required a lower dose of warfarin as compared with *1*1 carriers (35.0 [31.5–52.5] vs. 43.8 [35.0–60.2] mg/week, p=0.02; 35.0 [23.5–35.0] vs. 43.8 [35.0-60.2] mg/week, p<0.0001, respectively). Similarly, possession of G allele of GGCX c.2084+45 polymorphism was associated with lower warfarin dose (35.0 [26.3–39.2] vs. 45.5 [35.0–65.1] mg/week, p=0.03). No effect of CYP2C9*2,-*3 and GGCX c.2084+45G>C polymorphisms on acenocoumarol dosage was observed. Interestingly, carriers of CYP4F2 c.1297A variant required a higher dose of acenocoumarol and warfarin than non-carriers (43.8 [35.0–60.2] vs. 35.0 [35.0–52.5] mg/week, p=0.01; 35.0 [28.0–52.5] vs. 28.0 [28.0–42.0] mg/week, p=0.05). ConclusionsWe have shown for the first time, that besides VKORC1 and CYP2C9 genetic variants, the CYP4F2 c.1297A and GGCX c.2084+45G have a moderate effect on VKAs dose requirements in Slavic population from Central-Eastern Europe.

PW284 Improved Accuracy Of Anticoagulant Dose Prediction Using A Pharmacogenetic And Artificial Neural Network Based Method

Background The unpredictability of acenocoumarol dose needed to achieve target blood thinning level remains a challenge. We aimed to apply and compare a pharmacogenetic least-squares model (LSM) and artificial neural network (ANN) models for predictions of acenocoumarol dosing.

PKP-003 Genetic polymorphisms associated with the dose of acenocoumarol

BackgroundThe coumarins have a narrow therapeutic window and there is wide inter- and intra-individual variability in dose requirements. Therefore, patients are monitored by measuring the international normalised ratio (INR). Recent...

Influence of CYP2C9 polymorphism and phenytoin co-administration on acenocoumarol dose in patients with cerebral venous thrombosis

The study aimed at evaluating the contribution of genetic variations in the drug metabolizing enzyme, CYP2C9, and the influence of co-medication with the antiepileptic drug, phenytoin, to variability in acenocoumarol response, in patients with cerebral venous thrombosis (CVT). 476 acenocoumarol-treated CVT patients (153 males and 323 females) were genotyped for CYP2C9*2 and CYP2C9*3 polymorphisms by PCR-RFLP method. Mean acenocoumarol dose required for achieving and maintaining a stable international normalized ratio (INR) was calculated for different genotypes. The effect of co-administration with phenytoin was determined. Genotype distributions of CYP2C9 were as follows: 83%CYP2C9*1/*1, 8.6%CYP2C9*1/*3, 5.9%CYP2C9*1/*2, 1.9%CYP2C9*3/*3, 0.4%CYP2C9*2/*3 and 0.2%CYP2C9*2/*2. During the initiation phase of anticoagulation the CYP2C9*2 allele was independently associated with low acenocoumarol dose requirement (Adjusted OR 5.38; 95%CI 1.65-17.49; p=0.005). Similarly, the adjusted odds ratio for requiring a low dose during the induction phase in patients bearing the CYP2C9*3 allele was 12.79 (95%CI 4.74-34.57; p<0.0001). During the maintenance phase, CYP2C9*2 and CYP2C9*3 alleles were associated with 19-fold (Adjusted OR 19.67; 95%CI 2.46-157.19; p=0.005) and 11.9-fold odds (Adjusted OR 11.98; 95%CI 2.61-55.08; p=0.001) of requiring a low dose. Clinical covariates such as age, alcohol consumption, postpartum state and oral contraceptive intake also influenced acenocoumarol dosage. Co-medication with phenytoin was associated with lower dose requirement across genotypes during the initiation phase. However, during the maintenance phase, phenytoin-treated patients of all genotypes required higher doses of acenocoumarol. This study emphasizes the fact that polymorphisms in CYP2C9 gene and co-medication with phenytoin alter the anticoagulant effect of acenocoumarol.

Influence of Vitamin K Epoxide Reductase Complex 1 Gene Polymorphisms on Anticoagulation with Acenocoumarol in Patients with Cerebral Venous Thrombosis

Aims: Acenocoumarol, a commonly prescribed oral anticoagulant drug, exhibits wideinter-individual variability in response. This study aimed at evaluating the contribution of genetic variations in Vitamin K epoxide reductase complex, subunit 1 (VKORC1), to variability in the response to acenocoumarol, in patients with cerebral venous thrombosis (CVT). Place and Duration of Study: National Institute of Mental Health and Neuro Sciences, Bangalore, India, between September 2009 and January 2013. Methodology: 476 acenocoumarol-treated aseptic CVT patients (153 males, 323 females) were genotyped for VKORC1 -1639G>A and 1173C>T polymorphisms. Mean daily acenocoumarol dose for achieving and maintaining the optimum international normalized ratio (INR) was calculated for different genotypes. Results: Genotype distribution of VKORC1-1639G>A was as follows: 69.7% were wild, Original Research Article British Journal of Medicine & Medical Research, 4(4): 1069-1080, 2014 1070 25.6% heterozygous and 4.6%, mutant. Mean acenocoumarol dose required to achieve the optimum INR was lower in heterozygous (1.82±0.71mg/day) and homozygous mutants (1.75±0.69mg/day) when compared to wild type patients (2.31±0.89mg/day). Bearing the VKORC1 -1639A allele independently increased the odds of requiring a low dose (Adjusted OR 3.9; 95% CI 1.97-7.73; p A and 1173C>T were observed to be tightly linked (r 2 =0.98) and no difference in the genotype distributions was observed between the two polymorphisms. Factors such as age and co-medication with phenytoin were also found to influence the drug dosage. Conclusion: Our findings support the use of VKORC1 genotyping during anticoagulation with acenocoumarol in patients with CVT.

Improved accuracy of anticoagulant dose prediction using a pharmacogenetic and artificial neural network-based method

The unpredictability of acenocoumarol dose needed to achieve target blood thinning level remains a challenge. We aimed to apply and compare a pharmacogenetic least-squares model (LSM) and artificial neural network (ANN) models for predictions of acenocoumarol dosing. LSM and ANN models were used to analyze previously collected data on 174 participants (mean age: 67.45 SD 13.49years) on acenocoumarol maintenance therapy. The models were based on demographics, lifestyle habits, concomitant diseases, medication intake, target INR, and genotyping results for CYP2C9 and VKORC1. LSM versus ANN performance comparisons were done by two methods: by randomly splitting the data as 50% derivation and 50% validation cohort followed by a bootstrap of 200 iterations, and by a 10-fold leave-one-out cross-validation technique. The ANN-based pharmacogenetic model provided higher accuracy and larger R value than all other LSM-based models. The accuracy percentage improvement ranged between 5% and 24% for the derivation cohort and between 12% and 25% for the validation cohort. The increase in R value ranged between 6% and 31% for the derivation cohort and between 2% and 31% for the validation cohort. ANN increased the percentage of accurately dosed subjects (mean absolute error ≤1mg/week) by 14.1%, reduced the percentage of mis-dosed subjects (mean absolute error 2-3mg/week) by 7.04%, and reduced the percentage of grossly mis-dosed subjects (mean absolute error ≥4mg/week) by 24%. ANN-based pharmacogenetic guidance of acenocoumarol dosing reduces the error in dosing to achieve target INR. These results need to be ascertained in a prospective study.