Dabigatran (Pradaxa)

Dabigatran (Pradaxa)

(Boehringer Ingelheim)

It should be noted up front that while Dabigatran is indicated as an anticoagulation Rx for atrial fibrillation, it is not recommended for patient’s with concomitant valvular disease, and not indicated for anticoagulation therapy in patient’s receiving valve replacements or experiencing valve dysfunction.

Mechanism of Action

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

Pharmacodynamics

At recommended therapeutic doses, dabigatran etexilate prolongs the aPTT, ECT, and TT. With an oral dose of 150 mg twice daily the median peak aPTT is approximately 2x control. Twelve hours after the last dose the median aPTT is 1.5x control, with less than 10% of patients exceeding 2x control. In the RE-LY trial, the median (10th – 90th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 – 76) seconds. The median (10th – 90th percentile) trough ECT in patients receiving the 150 mg dose was 63 (44- 103) seconds.

The INR test is relatively insensitive to the activity of dabigatran and may or may not be elevated in patients on Pradaxa. When converting a patient from Pradaxa to warfarin therapy, the INR is unlikely to be useful until at least 2 days after discontinuation of Pradaxa.

Pharmacokinetics

Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran, the active moeity. Dabigatran is metabolized to four different acyl glucuronides and both the glucuronides and dabigatran have similar pharmacological activity. Pharmacokinetics described here refer to the sum of dabigatran and its glucuronides. Dabigatran displays dose-proportional pharmacokinetics in healthy subjects and patients in the range of doses from 10 to 400 mg.

Distribution

Dabigatran is approximately 35% bound to human plasma proteins. The red blood cell to plasma partitioning of dabigatran measured as total radioactivity is less than 0.3. The volume of distribution of dabigatran is 50-70 L. Dabigatran pharmacokinetics are dose proportional after single doses of 10-400 mg. Given twice daily, dabigatran’s accumulation factor is approximately two.

Elimination

Dabigatran is eliminated primarily in the urine. Renal clearance of dabigatran is 80% of total clearance after intravenous administration. After oral administration of radiolabeled dabigatran, 7% of radioactivity is recovered in urine and 86% infeces. The half-life of dabigatran in healthy subjects is 12 to 17 hours.

Metabolism

After oral administration, dabigatran etexilate is converted to dabigatran. The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to the active principal dabigatran is the predominant metabolic reaction. Dabigatran is not a substrate, inhibitor or inducer of CYP450 enzymes. Dabigatran is subject to conjugation forming pharmacologically active acyl glucuronides. Four positional isomers, l-O, 2-0, 3-0 and 4-O-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma.

Table: Estimated Pharmacokinetic Parameters of Dabigatran by Renal Function

Renal Function CrCl
(mL/min)
Increase in AUC Increase in Cmax t ½
(h)
Normal 80 1x 1x 13
Mild 50 1.5x 1.1x 15
Moderate 30 3.2x 1.7x 18

Hepatic Impairment

Administration of Pradaxa in patients with moderate hepatic impairment (Child-Pugh B) showed a large inter-subject variability, but no evidence of a consistent change in exposure or pharmacodynamics.

Source:

NEW DRUG REVIEWhttps://newdrugreview.com/index.php/anticoagulants/pradaxa-12-clinical-pharmacology

Effects on PT, pTT, fibrinogen

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Q & A with Dr Michael Ezekowitz

(https://www.theheart.org/article/1142899.do)


How swiftly does dabigatran reach therapeutic levels?

Dabigatran becomes therapeutic within 30 minutes to two hours of oral administration, so it is pretty immediate.

Are there any drug-drug interactions or contraindications that you want to highlight?

The only drug that is contraindicated is rifampicin, because it induces the p-glycoprotein enzyme and actually increases the removal of the drug by the gut from the blood via a complicated mechanism. But in all other respects, there are no other significant drug-drug interactions, and there are no warnings in the FDA label.

How long do you need to wait after stopping dabigatran before surgery can be performed?

Generally, if it’s elective surgery and the patient has normal kidney function, we recommend that he miss two doses of the drug. If the kidney function is abnormal, he should miss three and maybe four doses of the drug: in other words, two days’ worth of the medication.

Any specific recommendations for patients who have received a drug-eluting stent and are already taking both aspirin and clopidogrel?

About 8% of the patients who were in the RE-LY trial were being treated with clopidogrel; the use of clopidogrel at study entry was not a contraindication. As far as triple therapy is concerned, we don’t have data yet from the RE-LY trial on patients who were on triple therapy over the course of the trial; however, for the study as a whole, there was a bleeding advantage in favor of dabigatran over warfarin, particularly when it came to intracranial hemorrhages, so I doubt very much that dabigatran would be a disadvantage, compared with warfarin, for triple therapy. But this is a question that really needs to be definitively addressed at some point.

Do you have any insights into who could or should be switched off warfarin to this drug and any patients who shouldn’t?

Well, the decision to switch the patient from warfarin to dabigatran rests with the patient’s doctor and the patients themselves. There is a clear advantage to using dabigatran: you have a 34% reduction in stroke, a 60% reduction in intracranial bleeds, and fewer bleeds in general. The patients who are contraindicated are those patients who have a creatinine clearance of less than 15—those are patients who are generally headed toward dialysis—and also patients who have mechanical heart valves, were not entered into the trial and should not be treated with dabigatran. All the rest are certainly candidates for dabigatran therapy, and I anticipate that the uptake of the drug will be very rapid.