CLINICAL PHARMACOLOGY
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
coagulation markers such as aPTT, ECT, and TT. INR is relatively
insensitive to the exposure to dabigatran and cannot be interpreted
the same way as used for warfarin monitoring.
The aPTT test provides an approximation of PRADAXA’s
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 1. 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 PRADAXA is
not precisely known. In the RE-LY trial, the median (10th to 90th percentile) trough
aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.
Figure 1 Average Time Course for
Effects of Dabigatran on aPTT, Following Approved PRADAXA Dosing Regimens
in Patients with Various Degrees of Renal Impairment*
*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 (10th to
90th 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.
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 subjects and patients in the range of doses from 10 to
400 mg.
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, Cmax occurs
at 1 hour post-administration in the fasted state. Coadministration
of PRADAXA with a high-fat meal delays the time to Cmax by approximately 2 hours but has no effect on the bioavailability
of dabigatran; PRADAXA 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. PRADAXA 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. Dabigatran pharmacokinetics are dose proportional after single
doses of 10 to 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% in feces. 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, 1-O, 2-O, 3-O, and 4-O-acylglucuronide
exist, and each accounts for less than 10% of total dabigatran in
plasma.
Renal Impairment
An open,
parallel-group single-center study compared dabigatran pharmacokinetics
in healthy subjects and patients with mild to moderate renal impairment
receiving a single dose of PRADAXA 150 mg. Exposure to dabigatran
increases with severity of renal function impairment (Table 6). Similar
findings were observed in the RE-LY and RE-COVER trials.
Table 6 Impact of Renal Impairment on Dabigatran Pharmacokinetics
|
+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 (2.1, 2.2) and Use in Specific Populations ]. |
|
Renal Function
|
CrCl (mL/min)
|
Increase in
AUC
|
Increase in
Cmax
|
t1/2
(h)
|
|
Normal
|
≥ 80 |
1x |
1x |
13 |
|
Mild
|
50-80 |
1.5x |
1.1x |
15 |
|
Moderate
|
30-50 |
3.2x |
1.7x |
18 |
|
Severe+
|
15-30 |
6.3x |
2.1x |
27 |
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.
Drug Interactions
Impact of Other Drugs
on Dabigatran
P-gp Inducers
Rifampin: Rifampin 600 mg once daily for 7 days followed by a single dose of
dabigatran decreased its AUC and Cmax by 66%
and 67%, respectively. By Day 7 after cessation of rifampin treatment,
dabigatran exposure was close to normal [see Warnings and
Precautions and Drug Interactions (7) ].
P-gp Inhibitors
In studies with the P-gp inhibitors ketoconazole,
amiodarone, verapamil, and quinidine, the time to peak, terminal half-life,
and mean residence time of dabigatran were not affected. Any observed
changes in Cmax and AUC are described below.
Dronedarone: Simultaneous
administration of dabigatran etexilate and dronedarone (administered
once or twice daily) increases exposure to dabigatran by 70 to 140%
compared to dabigatran alone. The increase in exposure is only 30
to 60% higher compared to dabigatran alone when dronedarone is administered
2 hours after dabigatran etexilate.
Ketoconazole: Systemic ketoconazole increased dabigatran
AUC and Cmax values by 138% and 135%, respectively,
after a single dose of 400 mg, and 153%, and 149%, respectively, after
multiple daily doses of 400 mg.
Verapamil: When dabigatran etexilate was coadministered
with oral verapamil, the Cmax and AUC of dabigatran
were increased. The extent of increase depends on the formulation
of verapamil and timing of administration. If verapamil is present
in the gut when dabigatran is taken, it will increase exposure to
dabigatran with the greatest increase observed when a single dose
of immediate-release verapamil is given one hour prior to dabigatran
(AUC increased by a factor of 2.4). If verapamil is given 2 hours
after dabigatran, the increase in AUC is negligible. In the population
pharmacokinetics study from RE-LY, no important changes in dabigatran
trough levels were observed in patients who received verapamil. Similar
findings were observed in the RE-COVER study.
Amiodarone: When dabigatran etexilate
was coadministered with a single 600 mg oral dose of amiodarone, the
dabigatran AUC and Cmax increased by 58% and
50%, respectively. The increase in exposure was mitigated by a 65%
increase in the renal clearance of dabigatran in the presence of amiodarone.
The increase in renal clearance may persist after amiodarone is discontinued
because of amiodarone’s long half-life. In the population pharmacokinetics
study from RE-LY, no important changes in dabigatran trough levels
were observed in patients who received amiodarone.
Quinidine: Quinidine was given as
a 200 mg dose every 2 hours up to a total dose of 1000 mg. Dabigatran
etexilate was given over 3 consecutive days, the last evening dose
on Day 3 with or without quinidine pre-dosing. Concomitant quinidine
administration increased dabigatran’s AUC and Cmax by 53% and 56%, respectively.
Clarithromycin: Coadministered clarithromycin had
no impact on the exposure to dabigatran.
Ticagrelor: Administration
of ticagrelor modestly increases plasma concentrations of dabigatran
with the magnitude of increase dependent on the dose and timing of
ticagrelor administration. When dabigatran etexilate 110 mg twice
daily was coadministered with 90 mg oral ticagrelor twice daily, the
AUCτ,ss and Cmax,ss of
dabigatran increased by 26% and 29%, respectively. When coadministered
with a loading dose of 180 mg ticagrelor, the AUCτ,ss and Cmax,ss of dabigatran increased by 49%
and 65%, respectively; but when ticagrelor 180 mg was given 2 hours
after dabigatran, the AUCτ,ss and Cmax,ss of dabigatran increased by only 27% and 24%, respectively [see Warnings and Precautions and Drug Interactions].
Other Drugs
Clopidogrel: When dabigatran etexilate was given concomitantly with a loading
dose of 300 mg or 600 mg clopidogrel, the dabigatran AUC and Cmax increased by approximately 30% and 40%, respectively.
The concomitant administration of dabigatran etexilate and clopidogrel
resulted in no further prolongation of capillary bleeding times compared
to clopidogrel monotherapy. When comparing combined treatment and
the respective mono-treatments, the coagulation measures for dabigatran’s
effect (aPTT, ECT, and TT) remained unchanged, and inhibition of platelet
aggregation (IPA), a measurement of clopidogrel’s effect, remained
unchanged.
Enoxaparin: Enoxaparin 40 mg given subcutaneously for 3 days with the last dose
given 24 hours before a single dose of PRADAXA had no impact on the
exposure to dabigatran or the coagulation measures aPTT, ECT, or TT.
Diclofenac, Ranitidine,
and Digoxin:
None of these drugs alters exposure
to dabigatran.
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.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Dabigatran was not carcinogenic when administered
by oral gavage to mice and rats for up to 2 years. The highest doses
tested (200 mg/kg/day) in mice and rats were approximately 3.6 and
6 times, respectively, the human exposure at MRHD of 300 mg/day based
on AUC comparisons.
Dabigatran
was not mutagenic in in vitro tests, including bacterial
reversion tests, mouse lymphoma assay and chromosomal aberration assay
in human lymphocytes, and the in vivo micronucleus
assay in rats.
In the rat fertility
study with oral gavage doses of 15, 70, and 200 mg/kg, males were
treated for 29 days prior to mating, during mating up to scheduled
termination, and females were treated 15 days prior to mating through
gestation Day 6. No adverse effects on male or female fertility were
observed at 200 mg/kg or 9 to 12 times the human exposure at MRHD
of 300 mg/day based on AUC comparisons. However, the number of implantations
decreased in females receiving 70 mg/kg, or 3 times the human exposure
at MRHD based on AUC comparisons.
|
