acenocoumarol and Body-Weight

Numerous factors are well documented to affect the response to vitamin K antagonists (VKA), including dietary vitamin K, other drugs, age, pharmacogenetics, and disease states. Body weight is perhaps not as well known as a variable affecting VKA dose. Our aim was to review the literature regarding body weight and VKA dose requirements.. We reviewed the English-language literature via PubMed and Scopus using the search terms VKA, warfarin, acenocoumarol, phenprocoumon, fluindione, AND body weight.. Among 32 studies conducted since the widespread use of the international normalized ratio, 29 found a correlation with body weight or body surface area and VKA dose requirement. Warfarin was evaluated in 27 studies and acenocoumarol, phenprocoumon, or fluindione were assessed in 5 investigations.. Because of varying study methodologies, further study is warranted. Based on current evidence, clinicians should include body weight, along with other established variables when dosing VKA. Most important, obese and morbidly obese patients may require a 30% to 50% increase with the initial dosing of VKA.

Topics: Acenocoumarol; Anticoagulants; Body Weight; Comorbidity; Drug Dosage Calculations; Humans; Obesity; Obesity, Morbid; Phenindione; Phenprocoumon; Vitamin K; Warfarin

Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to fluindione and acenocoumarol. The aims of this study were to characterize the relationship between fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization.. Fluindione concentrations, S- and R-acenocoumarol concentrations, the INR and genotype data from healthy subjects were used to develop a population pharmacokinetic-pharmacodynamic model in Monolix software. Twenty-four White healthy subjects were enrolled in the pharmacogenetic study. The study was an open-label, randomized, two-period cross-over study. The subjects received two doses of an oral anticoagulant: 20 mg of fluindione (period A) or 4 mg of acenocoumarol (period B). The pharmacokinetics and pharmacodynamics were studied from day 2 to day 3.. A two-compartment model with a first-order input model was selected as the base model for the two drugs. The pharmacodynamic response was best described by an indirect action model with S-acenocoumarol concentrations and fluindione concentrations as the only exposure predictors of the INR response. Three covariates (CYP2C9 genotype, VKORC1 genotype and body weight) were identified as important predictors for the pharmacokinetic-pharmacodynamic model of S-acenocoumarol, and four covariates (CYP2C9 genotype, VKORC1 genotype, CYP1A2 phenotype and body weight) were identified as predictors for the pharmacokinetic-pharmacodynamic model of fluindione. Because some previous studies have shown a dose-response relationship between smoking exposure and the CYP1A2 phenotype, it was also noted that smokers have greater CYP1A2 activity.. During initiation of therapy, CYP2C9 and VKORC1 genetic polymorphisms are important predictors of fluindione and acenocoumarol pharmacokinetic-pharmacodynamic responses. Our result suggests that it is important to take the CYP1A2 phenotype into account to improve individualization of fluindione therapy, in addition to genetic factors.

Topics: Acenocoumarol; Adult; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Body Weight; Cross-Over Studies; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C9; Female; Genotype; Humans; International Normalized Ratio; Male; Mixed Function Oxygenases; Models, Biological; Phenindione; Polymorphism, Genetic; Smoking; Vitamin K Epoxide Reductases

Polymorphisms in CYP2C9 and VKORC1 influence patients' phenprocoumon (PHE) and acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patient's individual dose, we aimed to develop algorithms for PHE and ACE.. In two Dutch anticoagulation clinics, data on age, sex, height, weight, co-medication, coumarin derivative doses, and international normalized ratio values were obtained from 624 patients taking PHE and 471 taking ACE. Single nucleotide polymorphisms relevant to coumarin derivative dosing on the CYP2C9 and VKORC1 genes were determined. Using multiple linear regression, we developed genotype-guided and non-genotype-guided algorithms to predict the maintenance dose with patient characteristics and genetic information. In addition, loading doses were derived from the calculated maintenance doses. We performed external validation in an independent data set with 229 PHE and 168 ACE users. CYP2C9 and VKORC1 genotype, weight, height, sex, age, and amiodarone use contributed to the maintenance dose of PHE and ACE. The genotype-guided algorithms explained 55.9% (PHE) and 52.6% (ACE) of the variance of the maintenance dose, the non-genetic algorithms 17.3% (PHE) and 23.7% (ACE). Validation in an independent data set resulted in an explained variation of 59.4% (PHE) and 49.0% (ACE) for the genotype-guided algorithms and for 23.5% (PHE) and 17.8% (ACE) for the non-genotype-guided algorithms, without height and weight as parameters.. To our knowledge, these are the first genotype-guided loading and maintenance dose algorithms for PHE and ACE using large cohorts. The utility of these algorithms will be tested in randomized controlled trials.

Topics: Acenocoumarol; Administration, Oral; Adult; Aged; Algorithms; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Body Height; Body Weight; Cytochrome P-450 CYP2C9; Drug Dosage Calculations; Female; Genotype; Humans; International Normalized Ratio; Male; Middle Aged; Mixed Function Oxygenases; Pharmacogenetics; Phenprocoumon; Polymorphism, Genetic; Vitamin K Epoxide Reductases

A pharmacokinetic-pharmacodynamic (PK-PD) drug-drug interaction between acenocoumarol and amoxicillin + clavulanic acid antibiotic was assessed in eight healthy volunteers, using a population PK-PD) model. Each subject received at day 1 a single dose of 8 mg of acenocoumarol. Then 1 g of amoxicillin + 250 mg of clavulanic acid was given from days 3 to 9. On day 8, each subject received a single dose of 8 mg of acenocoumarol concomitantly with the antibiotic combination. Eleven blood samples were taken during 48 h following each acenocoumarol administration. Acenocoumarol plasma concentrations and prothrombin time were measured at each sampling time. We first identified the structural PK model by pooling data from this trial with individual data from other acenocoumarol PK trials. An indirect response model was used to fit PD data. Models were built using a non-linear mixed effect modelling approach with nonmem software. Covariates were tested on PK and PD parameters, including antibiotic treatment. Acenocoumarol PK data were fitted by a two-compartment, first-order input model with log normal inter-individual variability. Weight and antibiotic treatment were found to improve significantly the fit of PK data with a 15% decrease in acenocoumarol clearance with concomitant antibiotics (P < 0.05). An indirect response model was successfully applied to the PK-PD data of acenocoumarol. No covariate, including antibiotic treatment effect, significantly affected PT. Drug-drug interaction was demonstrated at the PK level, without any PD corollary.

Topics: Acenocoumarol; Adult; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Anticoagulants; Body Weight; Drug Interactions; Humans; Male; Models, Biological; Nonlinear Dynamics; Prothrombin Time; Young Adult

As long-term anticoagulant therapy with coumarin derivates like Sintrom becomes more and more important the question arises whether there is an interaction with a new drug like Ludiomil. An open, noncomparative trial was carried out with 20 patients receiving Sintrom (overall mean :3.0 mg/d, range :0 to 10 mg/d) for a period of 4 weeks, and in addition, during the second and third week Ludiomil (50 mg t. i. d.) orally. As a measurement of the efficacy of the antiocoagulant therapy, the correlation coefficients between the doses of Sintrom and the prothrombin value of the nex day were calculated for each patient and each week separately. An analysis of variance did not show any statistically significant difference between the correlation coefficients of the weeks with and without Ludiomil therapy, i.e. there is no change in the efficacy of the anticoagulant therapy. During the Ludiomil therapy the control of the anticoagulant therapy was slightly better, i.e. the fluctuations of the prothrombin values less, but statistically these differences were not significant. The plasma levels of Ludiomil in these patients were similar to thse found previously in both depressed and healthy volunteers.

Topics: Acenocoumarol; Anthracenes; Anticoagulants; Antidepressive Agents, Tricyclic; Blood Coagulation; Body Weight; Drug Interactions; Humans; Long-Term Care; Propylamines; Prothrombin Time