Warfarin pharmacokinetics and molecular data

Clinical Pharmacology
Warfarin sodium and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II - 60 hours, VII - 4 to 6 hours, IX - 24 hours, and X- 48 to 72 hours. The half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively. The resultant in vivo effect is a sequential depression of Factor VII, Protein C, Factor IX, Protein S, and Factor X and II activities. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. The vitamin promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins which are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the dosage administered. Therapeutic doses of Warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%.

An anticoagulation effect generally occurs within 24 hours after drug administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic Warfarin is 2 to 5 days. The effects of Warfarin sodium may become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.

Pharmacokinetics
Warfarin sodium is a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.

Absorption
Warfarin sodium is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours.

Distribution
There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of Warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-Warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but Warfarin has not been found in human milk (see WARNINGS: Lactation). Approximately 99% of the drug is bound to plasma proteins.

Metabolism
The elimination of Warfarin is almost entirely by metabolism. Warfarin sodium is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (Warfarin alcohols). The Warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of Warfarin that have been identified include dehydroWarfarin, two diastereoisomer alcohols, 4'-, 6-, 7-, 8- and 10-hydroxyWarfarin. The Cytochrome P-450 isozymes involved in the metabolism of Warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of Warfarin.

Excretion
The terminal half-life of Warfarin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-Warfarin is generally half that of S-Warfarin, thus as the volumes of distribution are similar, the half-life of R-Warfarin is longer than that of S-Warfarin. The half-life of R-Warfarin ranges from 37 to 89 hours, while that of S-Warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little Warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

Elderly
Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of Warfarin. The cause of the increased sensitivity to the anticoagulant effects of Warfarin in this age group is unknown. This increased anticoagulant effect from Warfarin may be due to a combination of pharmacokinetic and pharmacodynamic factors. Racemic Warfarin clearance may be unchanged or reduced with increasing age. Limited information suggests there is no difference in the clearance of S-Warfarin in the elderly versus young subjects. However, there may be a slight decrease in the clearance of R-Warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of Warfarin is usually required to produce a therapeutic level of anticoagulation.

Asians
Asian patients may require lower initiation and maintenance doses of Warfarin. One non-controlled study conducted in 151 Chinese outpatients reported a mean daily Warfarin requirement of 3.3 ± 1.4 mg to achieve an INR of 2 to 2.5. These patients were stabilized on Warfarin for various indications. Patient age was the most important determinant of Warfarin requirement in Chinese patients with a progressively lower Warfarin requirement with increasing age.

Renal Dysfunction
Renal clearance is considered to be a minor determinant of anticoagulant response to Warfarin. No dosage adjustment is necessary for patients with renal failure.

Hepatic Dysfunction
Hepatic dysfunction can potentiate the response to Warfarin through impaired synthesis of clotting factors and decreased metabolism of Warfarin.

The administration of Warfarin sodium via the intravenous (I.V.) route should provide the patient with the same concentration of an equal oral dose, but maximum plasma concentration will be reached earlier. However, the full anticoagulant effect of a dose of Warfarin may not be achieved until 72 to 96 hours after dosing, indicating that the administration of I.V. Warfarin sodium should not provide any increased biological effect or earlier onset of action.

ATRIAL FIBRILLATION (AF)
In five prospective randomized controlled clinical trials involving 3711 patients with non-rheumatic AF, Warfarin significantly reduced the risk of systemic thromboembolism including stroke (See Table 1). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%) which stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6 to 2.7% (see Table 1). Meta-analysis findings of these studies revealed that the effects of Warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0 to 4.5) or low INR (1.4 to 3.0). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available.

WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks postinfarction treated with Warfarin to a target INR of 2.8 to 4.8. [But note that a lower INR was achieved and increased bleeding was associated with INR's above 4.0; (see DOSAGE AND ADMINISTRATION)]. The primary endpoint was a combination of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months.

WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label randomized study of 3630 patients hospitalized for acute myocardial infarction treated with Warfarin target INR 2.8 to 4.2, aspirin 160 mg/day, or Warfarin target INR 2.0 to 2.5 plus aspirin 75 mg/day prior to hospital discharge. There were approximately four times as many major bleeding episodes in the two groups receiving Warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus Warfarin than among those receiving Warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years.

MECHANICAL AND BIOPROSTHETIC HEART VALVES
In a prospective, randomized, open label, positive-controlled study2 in 254 patients, the thromboembolic-free interval was found to be significantly greater in patients with mechanical prosthetic heart valves treated with Warfarin alone compared with dipyridamole-aspirin (p<0.005) and pentoxifylline-aspirin (p<0.05) treated patients. Rates of hromboembolic events in these groups were 2.2, 8.6, and 7.9/100 patient years, respectively. Major bleeding rates were 2.5, 0.0, and 0.9/100 patient years, respectively.

In a prospective, open label, clinical trial comparing moderate (INR 2.65) vs. high intensity (INR 9.0) Warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events/100 patient years, respectively). Major bleeding was more common in the high intensity group (2.1 events/100 patient years) vs. 0.95 events/100 patient years in the moderate intensity group3.

In a randomized trial in 210 patients comparing two intensities of Warfarin therapy (INR 2.0 to 2.25 vs. INR 2.5 to 4.0) for a three month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively and minor embolic events 10.8% vs. 10.2%, respectively). Major bleeding complications were more frequent with the higher intensity (major hemorrhages 4.6%) vs. none in the lower intensity4.