PK & PD
- Pharmacodynamics13,3,14
- Pharmacokinetics
- Long-Term Studies1
- Acenocoumarol/Nicoumalone inhibits the synthesis of clotting factors as reflected by an increase in prothrombin time.
- Acenocoumarol/Nicoumalone has a rapid onset of action, a long duration of action, maintaining the effect for 24 hours and the reversal of coagulation parameters following withdrawal of the drug was rapid.
The increase in prothrombin time reaches a maximum after 36–48 hours after the administration of acenocoumarol/nicoumalone.
Patients receiving acenocoumarol/nicoumalone were found to maintain their prothrombin time within the accepted therapeutic levels (10–30% of normal) 91% of the time.
When one dose of acenocoumarol/nicoumalone was erroneously omitted, the effects of the drug were found to reverse rapidly, with the prothrombin time returning towards normalcy (32–80%) in about 24 hours. It is reported that the prothrombin time normalizes within 36-48 hours.
Acenocoumarol/Nicoumalone that is used clinically is a racemic mixture of equal quantities of R(+) and S(-) enantiomers. Studies have shown that unlike warfarin and phenprocoumon (for which the S(-) enantiomer is active), the R(+) enantiomer of acenocoumarol/nicoumalone is pharmacologically active.
Studies have shown that the anticoagulant activity of acenocoumarol/nicoumalone resides in the drug per se and not in its metabolites.
Acenocoumarol/Nicoumalone, a new coumarin derivative, represents a step forward in the search for the ideal anticoagulant.
Metabolism14,17,18
- Acenocoumarol/Nicoumalone is extensively metabolized, although the metabolites appear to be pharmacologically inactive in man.
- Metabolism occurs through reduction and oxidation of acenocoumarol/nicoumalone.
- Amino, acetoamido and alcohol metabolites are found in the plasma.
Distribution17
- Over 98% of acenocoumarol/nicoumalone 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.
- It crosses the placenta and is excreted in very small quantities into breast milk.
Absorption14,17
- Following oral administration, acenocoumarol/nicoumalone 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 10 mg.
- The area under curve (AUC) values are proportional to the size of the dose over a dosage range of 8 to 16 mg.
- No correlation between plasma concentrations of acenocoumarol/nicoumalone and the apparent prothrombin levels can be established, due to the variation of plasma drug concentrations between patients.
- Plasma drug concentrations are generally higher in patients of 70 years or over when compared with younger patients, after the same dose.
Elimination17
- Over 98% of acenocoumarol/nicoumalone 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.
- It crosses the placenta and is excreted in very small quantities into breast milk. The elimination half-life of acenocoumarol/nicoumalone from the plasma is 8 to 11 hours.
- 29% is excreted in the feces and 60% in the urine, with less than 0.2% of the dose renally excreted being unchanged.
- Acenocoumarol/Nicoumalone is extensively metabolized, although the metabolites appear to be pharmacologically inactive in man.
- Metabolism occurs through reduction and oxidation of acenocoumarol/nicoumalone.
- Amino, acetoamido and alcohol metabolites are found in the plasma.
- Over 98% of acenocoumarol/nicoumalone 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.
- It crosses the placenta and is excreted in very small quantities into breast milk.
- Following oral administration, acenocoumarol/nicoumalone 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 10 mg.
- The area under curve (AUC) values are proportional to the size of the dose over a dosage range of 8 to 16 mg.
- No correlation between plasma concentrations of acenocoumarol/nicoumalone and the apparent prothombin levels can be established, due to the variation of plasma drug concentrations between patients.
- Plasma drug concentrations are generally higher in patients of 70 years or over when compared with younger patients, after the same dose.
- Over 98% of acenocoumarol/nicoumalone 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.
- It crosses the placenta and is excreted in very small quantities into breast milk. The elimination half-life of acenocoumarol/nicoumalone from the plasma is 8 to 11 hours.
- 29% is excreted in the feces and 60% in the urine, with less than 0.2% of the dose renally excreted being unchanged.
Acenocoumarol/Nicoumalone has been in clinical use for over 50 years and has undergone extensive clinical investigation.
In long term studies of up to 10 years, acenocoumarol/nicoumalone has been shown to preserve its efficacy and safety. The patients were found to maintain the international normalized ratio (INR) within the therapeutic range, without significant fluctuations.
Ten-year experience with acenocoumarol/nicoumalone treatment in an ambulatory cohort of Spanish patients
Trullas-Vila JC et al., J Thromb Thrombolysis. 2009 Nov;28(4):436-43.
To analyze incidence of hemorrhagic and thrombotic events in a series of ambulatory patients receiving acenocoumarol/nicoumalone in a rural area of Spain (1997-2007).
Out of 1,544 patients, 1,086 are receiving acenocoumarol/nicoumalone at present (2% of the region's population). The total follow-up was 5,462 patients-years.
- Median age was 74 years.
- INR therapeutic range was 2.0-3.0 in 82.5%.
- Atrial fibrillation was the most frequent indication (73%).
- Incidence of hemorrhagic events was 2.27 patients-year.
- Incidence of thrombotic events was 0.2/100 patients-year.
- Age and therapeutic ranges of INR were not associated with increased risk of bleeding.
2% of the population is receiving acenocoumarol/nicoumalone. Incidence of hemorrhagic and thrombotic events was low.