Prescription Drug Information: Dabigatran Etexilate (Page 5 of 8)

11 DESCRIPTION

The chemical name for dabigatran etexilate mesylate, a direct thrombin inhibitor, is N-[[2-[[[4-[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-β-alanine ethyl ester, methanesulfonate. The empirical formula is C 34 H 41 N 7 O 5 .CH 3 SO 3 H and the molecular weight is 723.86 (mesylate salt), 627.75 (free base). The structural formula is:

Dabigatranstructure
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Dabigatran etexilate mesylate is a yellow-white to yellow color powder. Sparingly soluble in methanol.

Dabigatran etexilate capsules are supplied in 75 mg, and 150 mg strengths for oral administration. Each capsule contains dabigatran etexilate mesylate as the active ingredient: 150 mg dabigatran etexilate (equivalent to 172.95 mg dabigatran etexilate mesylate), or 75 mg dabigatran etexilate (equivalent to 86.48 mg dabigatran etexilate mesylate) along with the following inactive ingredients: hydroxypropyl cellulose, hypromellose, sugar spheres (sucrose and corn starch), talc and tartaric acid. The capsule shell is composed of iron oxide red, iron oxide yellow, hypromellose and titanium dioxide. The capsules are printed with black ink containing black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, TT, and dTT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring.
Adults
The aPTT test provides an approximation of dabigatran etexilate capsules anticoagulant effect. The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 2. The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT. While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of dabigatran etexilate capsules is not precisely known. In the RE-LY trial, the median (10 th to 90 th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds. Figure 2 Average Time Course for Effects of Dabigatran on aPTT, Following Approved Dabigatran Etexilate Capsules Dosing Regimens in Adult Patients with Various Degrees of Renal Impairment*

dabigatrancapfigure2
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*Simulations based on PK data from a study in subjects with renal impairment and PK/aPTT relationships derived from the RE-LY study; aPTT prolongation in RE-LY was measured centrally in citrate plasma using PTT Reagent Roche Diagnostics GmbH, Mannheim, Germany. There may be quantitative differences between various established methods for aPTT assessment.
The degree of anticoagulant activity can also be assessed by the ecarin clotting time (ECT). This test is a more specific measure of the effect of dabigatran than activated partial thromboplastin time (aPTT). In the RE-LY trial, the median (10 th to 90 th percentile) trough ECT in patients receiving the 150 mg dose was 63 (44 to 103) seconds.
Cardiac Electrophysiology
No prolongation of the QTc interval was observed with dabigatran etexilate at doses up to 600 mg.
Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

12.3 Pharmacokinetics

Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran, the active moiety. 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 adult subjects and adult patients in the range of doses from 10 to 400 mg. Given twice daily, dabigatran’s accumulation factor in adults is approximately two.
Absorption
The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3% to 7%. Dabigatran etexilate is a substrate of the efflux transporter P-gp. After oral administration of dabigatran etexilate in healthy volunteers, C max occurs at 1-hour post-administration in the fasted state. Coadministration of dabigatran etexilate capsules with a high-fat meal delays the time to C max by approximately 2 hours but has no effect on the bioavailability of dabigatran; dabigatran etexilate capsules may be administered with or without food.
The oral bioavailability of dabigatran etexilate increases by 75% when the pellets are taken without the capsule shell compared to the intact capsule formulation based on a single-dose relative bioavailability study.
Dabigatran etexilate capsules should therefore not be broken, chewed, or opened before administration.
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 to 70 L.
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% in feces. The half-life of dabigatran in healthy adult 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, 1-O, 2-O, 3-O, and 4-O-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma.
Specific Populations
Renal Impairment
An open, parallel-group, single-center study compared dabigatran pharmacokinetics in healthy adult subjects and adult patients with mild to moderate renal impairment receiving a single dose of dabigatran etexilate capsules 150 mg. Exposure to dabigatran increases with severity of renal function impairment (Table 10). Similar findings were observed in the RE-LY, and RE-COVER trials.
Table 10 Impact of Renal Impairment on Dabigatran Pharmacokinetics

Renal Function CrCl (mL/min) Increase in AUC Increase in C max t 1/2 (h)
Normal ≥80 1x 1x 13
Mild 50 to 80 1.5x 1.1x 15
Moderate 30 to 50 3.2x 1.7x 18
Severe + 15 to 30 6.3x 2.1x 27

+ Patients with severe renal impairment were not studied in RE-LY, and RE-COVER. Dosing recommendations in subjects with severe renal impairment are based on pharmacokinetic modeling [see Dosage and Administration ( 2.2, 2.4) and Use in Specific Populations ( 8.6)].
Hepatic Impairment
Administration of dabigatran etexilate capsules in adult 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.
Drug Interactions
A summary of the effect of coadministered drugs on dabigatran exposure in healthy adult subjects is shown in Figures 3.1 and 3.2. Figure 3.1 Effect of P-gp Inhibitor or Inducer (rifampicin) Drugs on Peak and Total Exposure to Dabigatran (Cmax and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90% Confidence Interval (90% CI). The Perpetrator and Dabigatran Etexilate Dose and Dosing Frequency are given as well as the Time of Perpetrator Dosing in Relation to Dabigatran Etexilate Dose (Time Difference)

dabigatrancapfigure3-1
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Figure 3.2 Effect of Non-P-gp Inhibitor or Inducer, Other Drugs, on Peak and Total Exposure to Dabigatran (C max and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90% Confidence Interval (90% CI). The Perpetrator and Dabigatran Etexilate Dose and Dosing Frequency are given as well as the Time of Perpetrator Dosing in Relation to Dabigatran Etexilate Dose (Time Difference)

dabigatrancapfigure3-2
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In RE-LY, dabigatran plasma samples were also collected. The concomitant use of proton pump inhibitors, H2 antagonists, and digoxin did not appreciably change the trough concentration of dabigatran.
Impact of Dabigatran on Other Drugs
In clinical studies exploring CYP3A4, CYP2C9, P-gp and other pathways, dabigatran did not meaningfully alter the pharmacokinetics of amiodarone, atorvastatin, clarithromycin, diclofenac, clopidogrel, digoxin, pantoprazole, or ranitidine. Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

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