phenprocoumon 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

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

According to a pharmacokinetic model, the adjustment of a phenprocoumon (PPC) standard dosage based on experimentally determined means values of the parameters volume of distribution and biological half-life will yield in more than 50% of the individuals the desired plasma PPC concentration. In 25 patients it was tested, whether the thus derived loading and maintenance doses, 376.8 and 35.2 micrograms PPC per kg b. wt., resp., actually lead to the predicted optimum plasma PPC concentration of 2.0 micrograms/ml. After initiating dosage, the plasma PPC concentrations were determined over a time period of 30 days. As predicted by the model, in 72% of the patients the average steady-state plasma PPC concentrations were within the range of 1.7 and 2.3 micrograms/ml. The data obtained were used to newly calculate mean values of the volume of distribution, the biological half-life, and the total body clearance of PPC. The mean biological half-life of PPC derived was somewhat shorter than that used for the calculation of the standard dose. Quick-values were estimated concomitantly with the plasma PPC concentrations. They revealed an optimum anticoagulation (15-25%) in 96% of the patients.

Topics: 4-Hydroxycoumarins; Adult; Aged; Body Weight; Drug Administration Schedule; Drug Tolerance; Female; Humans; Male; Middle Aged; Models, Biological; Phenprocoumon