Dabigatran etexilate (Pradaxa) is an oral anticoagulant (direct inhibitor of factor IIa, thrombin) approved by the FDA in 2010 as an alternative to warfarin. The indication is to reduce the risk of stroke and systemic embolism in persons with nonvalvular atrial fibrillation. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, dabigatran at a dose of 150 mg bid was statistically superior to warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation and had a lower non-statistically significant rate of major bleeding.⁽¹⁾ The FDA approved dose is 150 mg twice daily for persons with creatinine clearance greater than 30 mL/min. Dabigatran is eliminated primarily by the kidneys and reduced renal function will result in drug accumulation. For persons with creatinine clearance from 15 to 30 mL/min, a dose of 75 mg mg twice daily is available. When the creatinine clearance is less than 15 mL/min, the drug should not be administered.

One of the promises of new oral anticoagulants is that they will be less susceptible to drug, disease and food interactions that have been so problematic with warfarin. However, it appears that dabigatran as well other novel anticoagulants being developed won't entirely eliminate these types of interactions. Therefore health care providers prescribing dabigatran should be aware of its interactions especially because antithrombotic therapy always involves a balance between thromboembolism prevention and bleeding risk.

Dabigatran etexilate is a pro-drug that has a low (3%-7%) bioavailability. Once dabigatran etexilate is absorbed, the pro-drug is hydrolyzed to the active drug, dabigatran, by carboxylesterases in the bloodstream (Figure 1). Dabigatran etexilate is a substrate of the efflux transporter P-glycoprotein (P-gp), but dabigatran, the active drug, is not. P-gp is present on the luminal side of absorptive cells in the small intestine and takes drug molecules from the cell cytoplasm and transports them back into the intestinal lumen for excretion. For some orally administered drugs such as dabigatran etexilate that are substrates for P-gp, this transporter limits the drug’s bioavailability. Other P-gp substrates include digoxin and clopidogrel. P-gp inducers or inhibitors can alter the absorption of dabigatran etexilate during the drug’s pass through intestinal epithelium. Co-administration of an inducer of P-gp will reduce the bioavailability of a substrate drug by enhancing drug efflux back into the intestinal lumen; whereas an inhibitor of P-gp will increase bioavailability of a P-gp substrate by reducing drug efflux.

P-gp inducers include rifampin, carbamazepine, tipranavir and St. John’s wort. According to the FDA labeling, the only drug contraindicated with dabigatran is rifampin, which reduced the serum concentration of dabigatran by 66%.⁽²⁾ P-gp inhibitors include amiodarone, ketoconazole, quinidine, verapamil, diltiazem, cyclosporine, itraconazole, propafenone, ritonavir and dronedarone. Thus, concomitant administration of dabigatran etexilate (a P-gp substrate) along with dronedarone (a P-gp inhibitor) will increase bioavailability of dabigatran etexilate and the plasma concentration of dabigatran. However, staggered administration of dabigatran etexilate more than 2 hours before a P-gp inhibitor or inducer should minimize the effect on dabigatran etexilate absorption because once dabigatran etexilate is absorbed and converted to the active moiety, it is no longer susceptible to P-gp interactions. Notably in the prescribing information for both Multaq (dronedarone) and Pradaxa (dabigatran etexilate), the combination is not contraindicated and no dose adjustment is recommended during concomitant use of Pradaxa and Multaq.^{(2, 3)}

In a study conducted by the manufacturer of dronedarone (Sanofi-Aventis), exposure to dabigatran was 1.7- to 2-fold higher when it was co-administered with dronedarone than when it was administered alone (3). This study was conducted in 16 healthy subjects (ages, 18 and 45 years, 81.3% males) who were coadministered dabigatran etexilate 150 mg once daily (QD) and dronedarone 400 mg twice daily (BID) for 4 days. Repeated doses of dronedarone etexilate increased the dabigatran maximum plasma concentration (Cmax) by 1.73 -fold (90% confidence intervals [CIs]: 1.54 - 1.93 - fold) and the area under the concentration vs. time curve from 0 - 24 hours (AUC 0 – 24) by 1.99 -fold (90% CI: 1.79 - 2.21 -fold). Consistent with the observed pharmacokinetic interaction, the ecarin clotting time was increased by 1.5 (90% CI, 1.37 - 1.64) during co-administration of dronedarone with dabigatran etexilate. No bleeding complications were reported.

A phase 1 study (NCT01306162) sponsored by Boehringer Ingelheim assessing the bioavailability of dabigatran after concomitant administration of dronedarone also has been performed.⁽⁴⁾ According to ClinicalTrials.gov, this study was completed but no study results are available. There are 5 arms of this open-label, crossover study in healthy subjects (planned enrollment 36 subjects; 18-50 years of age, of either gender): dabigatran etexilate 150 mg as single dose; dabigatran etexilate 150 mg plus dronedarone 400 mg as single dose (with and without staggered administration); dabigatran etexilate 150 mg single dose plus dronedarone 400 mg bid (with and without staggered administration). Measurements were to include: AUC and Cmax of total and free dabigatran in plasma. This study should provide further data on the interaction between the 2 drugs and the effect of concomitant versus staggered drug administration.

Other P-gp inhibitors including verapamil and amiodarone increase the AUC of dabigatran from about 50% to over 200% ⁽²⁾ 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 etexilate 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 etexilate (AUC increased by a factor of 2.4). Administration of dabigatran etexilate 2 hours before verapamil completely avoided the interaction. 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. In the RE-LY trial, no important changes in dabigatran plasma levels were observed in patients who received verapamil or amiodarone. Dose adjustment has not been recommended in patients receiving dabigatran etexilate along with verapamil, amiodarone or combined amiodarone and verapamil.

Of note, digoxin also is a substrate for P-gp. Dronedrone increased digoxin exposure by 2.5-fold by inhibiting the P-gP transporter. When digoxin is co-administered with dronedarone, labeling recommendations for Multaq indicate that the digoxin dose should be halved and digoxin serum levels should be monitored closely.⁽³⁾

What about interactions via P-gp with other approved and investigational antithrombotic agents that might be alternatives to dabigatran etexilate in patients with atrial fibrillation? Although numerous drug, food and disease interactions are well recognized with warfarin, P-gp interactions with warfarin do not seem to be clinically important. Warfarin is well absorbed from the intestine with over 90% bioavailability, making it unlikely that intestinal P-GP affects the absorption of warfarin to a great extent.⁽⁵⁾ P-gp may contribute to warfarin disposition via a P-gp effect in hepatocytes. Rivaroxaban and apixaban are investigational, selective oral, direct, factor Xa inhibitors undergoing clinical development as alternatives to warfarin. Interestingly rivaroxaban, is a substrate for P-gp, but P-gp-related drug interactions with apixaban have not been reported.⁽⁶⁾

In summary, a pharmcokinetic and pharmacodynamic drug interaction exists between dabigatran etexilate and dronedarone related to the P-gp drug efflux transporter mechanism in the intestine. Dabigatran etexilate is a substrate for and dronedarone is an inhibitor of P-gp. When the 2 drugs were co-administered to young, healthy subjects, exposure to dabigatran was increased by 1.7- to 2.0-fold and the ecarin clotting time was increased by 1.5-fold. However, the clinical significance of this interaction remains uncertain in the population of patients with nonvalvular atrial fibrillation for whom both drugs are indicated. Whether use of this combination results in an increased risk of bleeding complications is unclear. Thus far, no such alerts have been reported on the FDA Medwatch site.⁽⁷⁾ Neither the FDA nor either pharmaceutical manufacturer has recommended a dosage adjustment of dabigatran etexilate when co-administered with dronedarone. Administration of dabigatran etexilate more than 2 hours before a P-gp inhibitor, such as dronedarone, should minimize the effect of the inhibitor on dabigatran etexilate absorption and dabigatran exposure. Therefore, it seems prudent to advise patients being prescribed both drugs to take dabigatran etexilate at least 2 hours before dronedarone. Patients stabilized on dabigatran should be monitored for bleeding if dronedarone is added to their drug regimen. Potential drug interactions remain an important safety consideration in clinical practice when prescribing new and old anticoagulants.

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References

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
2. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2011
3. Multaq [package insert]. Bridgewater, NJ: sanofi-aventis U.S.; 2011.
4. http://clinicaltrials.gov/ct2/show/NCT01306162 (Accessed on July 15, 2011).
5. Hardman JG, Limbird LE, Goodman Gilman A (eds). Goodman and Gilman’s. The Pharmacological Basis of Therapeutics, 10th edn McGraw- Hill Professional: New York 2001.
6. Walenga JM, Adiguzel C. Drug and dietary interactions of the new and emerging oral anticoagulants. Int J Clin Pract. 2010;64:956-67.
7. MedWatch: The FDA Safety Information and Adverse Event Reporting Program (Accessed on July 15, 2011) http://google2.fda.gov/search?q=dronedarone%2C+dabigatran&x=8&y=12&client=FDAgov&proxystylesheet=FDAgov&output=xml_no_dtd&sort=date%253AD%253AL%253Ad1&site=FDAgov-MedWatch-Safety

Keywords: Anticoagulants, Atrial Fibrillation, Biological Availability, ATP Binding Cassette Transporter, Subfamily B, Member 1, Prodrugs, Rifampin, Stroke, Thromboembolism

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