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Acenocoumarol

Brand names: SINTROM

Pharmacodynamic Properties

Acenocoumarol is a coumarin derivative and functions as vitamin K antagonist. Vitamin K antagonists produce their anticoagulant effect by inhibition of the vitamin K-epoxide-reductase with a subsequent reduction of the gammacarboxylation of certain glutamic acid molecules which are located at several sites near the terminal end both of coagulation factors II (prothrombin), VII, IX, and X and of protein C or its cofactor protein S. This gamma-carboxylation has a significant bearing on interaction of the aforementioned coagulation factors with Calcium ions. Without this reaction, blood clotting cannot be initiated.

Depending on the initial dosage, acenocoumarol prolongs the thromboplastin time within approximately 36 to 72 hours. Following withdrawal of Sinthrome, the thromboplastin time usually reverts to normal after a few days.

Pharmacokinetic Properties

Absorption

Acenocoumarol, is a racemic mixture of the optical R(+) and S(-) enantiomers.

Following oral administration, acenocoumarol is rapidly absorbed; at least 60% of the administered dose is systemically available. Peak plasma concentrations are achieved within 1 to 3 hours after a single dose of 10mg and AUC values are proportional to the size of the dose over a dosage range of 8 to 16mg.

No correlation between plasma concentrations of acenocoumarol and the apparent prothombin levels can be established, due to the variation of plasma drug concentrations between patients.

Distribution

Over 98% of acenocoumarol is protein-bound, mainly to albumin. The calculated apparent volume of distribution is 0.16- 0.18 L/kg for the R(+) enantiomer and 0.22-0.34 L/kg for the S(-) enantiomer.

Biotransformation

Acenocoumarol is extensively metabolised, 6- and 7-hydroxylation of both enantiomers of acenocoumarol are the major metabolites and the cytochrome P450 2C9 is the major catalyst for the formation of these four metabolites. Other enzymes involved in the metabolism of ®-acenocoumarol are CYP1A2 and CYP2C19. By reduction of the keto group two different carbinol metabolites are formed. Reduction of the nitro group results in an amino metabolite. None of these metabolites contribute to the anticoagulant activity of the parent drug in man, but they are all active in an animal model. CYP2C9-related genetic variability accounts for 14% of the inter-individual variability in acenocoumarol pharmacodynamics response.

Elimination

The elimination half-life of acenocoumarol from the plasma is 8 to 11 hours. The apparent plasma clearance amounts to 3.65 L/h after oral administration. The total plasma clearance of the (+) enantiomer of acenocoumarol, which possesses significantly higher anticoagulant activity, is much lower than that of the S(-) enantiomer.

29% is excreted in the faeces and 60% in the urine, with less than 0.2% of the dose renally excreted being unchanged.

Special Populations

Geriatric Patients

Plasma drug concentrations are generally higher in patients of 70 years or over when compared with younger patients, after the same dose.

Renal impairment

No clinical pharmacokinetic information of acenocoumarol in renal impairment is available. Based on the urinary excretion of acenocoumarol, the possibility of accumulation of metabolites in impaired renal function cannot be excluded. Therefore usage of acenocoumarol is contraindicated in patient with severe renal impairment and caution should be exercised in patients with mild to moderate renal impairment.

Hepatic impairment

No clinical pharmacokinetic information of acenocoumarol in hepatic impairment is available. Based on the metabolism of acenocoumarol, and possible reduced enzyme activities, CYP2C9, CYP1A2 and CYP3A4, clearance is likely to be reduced. Therefore usage of acenocoumarol is contraindicated in patients with severe hepatic impairment and caution should be exercised in patients with mild to moderate hepatic impairment.

Ethnicity

CYP2C9 enzyme systems are polymorphically expressed and the frequency of these in population differs. In Caucasians, occurrence of CYP2C9*2 and CYP2C9*3 frequencies are 12 and 8%, respectively. Patients with one or more of these variant CYP2C9 alleles have decreased clearance of S-acenocoumarol. In African patients, CYP2C9*2 and CYP2C9*3 occur at much lower allele frequencies 1-4% and 0.5-2.3%, respectively compared to Caucasians. Japanese population had lower allelic frequencies of 0.1% and 1-6% for CYP2C9*2 and CYP2C9*3, respectively].

The maintenance dose of acenocoumarol differs based on the genotype.

Detailed information of mean and median maintenance dose based on CYP2C9 genotype is given in the table below:

Table 1. CYP2C9 genotype and maintenance dose of acenocoumarol

GenotypeNMean dose (mg/week)SDMedian dose (mg/week)Range
CYP2C9*116917.18.715.82.3-61
CYP2C9*29014.46.313.53.5-37.5
CYP2C9*34811.05.110.52.3-22

Preclinical Safety Data

Toxicity

After a single (acute) oral and/or intravenous dose, acenocoumarol showed a low degree of toxicity in mice, rats, and rabbits. In dogs, high acute oral toxicity was seen.

In repeated-dose studies, the liver is suggested to be the main target organ in the toxicity of coumarin derivatives including acenocoumarol. The administration of these substances at excessive pharmacological doses can cause haemorrhages.

Reproduction toxicity, teratogenicity

No reproductive toxicity studies were performed with acenocoumarol. However, placental and transplacental interference with vitamin K dependent coagulation factors may give rise to embryonic or foetal anomalies and neonatal haemorrhages both in animals and in humans (see section 4.6 Fertility, pregnancy and lactation).

Mutagenicity

From investigations on bacterial and mammalian cell systems in vitro, including a DNA repair assay on rat hepatocytes, it can be concluded that acenocoumarol and/or its metabolites did not exert any mutagenic effects. An in vitro study on human lymphocytes has shown some mild mutagenic activity at a concentration of acenocoumarol, 500 to 1000 times higher than concentrations determined in human plasma after medication with acenocoumarol.

Carcinogenicity

No lifetime-exposure studies were carried out in animals with acenocoumarol.

Coumarin, induced an increase in the incidence of lung and benign liver tumours in mice, and liver and benign kidney tumours in rats. Liver tumours in rats and lung tumours in mice are understood to be associated with species-specific metabolic pathways in these species. Hepatoxicity of coumarin and its derivatives in the rat is understood to be associated with enzyme induction and the metabolic pathway of coumarin and/or its metabolites peculiar to this rodent species. Renal tumours observed in male mice are considered to be a species-specific effect.

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