Pharmacokinetics of dronedarone
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1
Aristotle University of Thessaloniki, Second Cardiology Department, Greece
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2
Aristotle University of Thessaloniki, Department of Pharmacology, Greece
Introduction. Dronedarone is an antiarrhythmic agent recently approved by the United States Food and Drug Administration for the reduction of cardiovascular-related hospitalizations in patients with paroxysmal or persistent atrial fibrillation or atrial flutter. The drug is a derivative of amiodarone and has been modified to reduce the organ toxicities frequently encountered with amiodarone. Dronedarone exerts its antiarrhythmic effects through multichannel blockade of the sodium, potassium, and calcium channels and also possesses antiadrenergic activity, thereby exhibiting pharmacologic effects of all four Vaughan Williams classes of antiarrhythmics.
Pharmacokinetics. Dronedarone is well absorbed after oral administration (70% - 94%), and absorption increases 2- to 3-fold when it is taken with food. Dronedarone undergoes significant first-pass metabolism that reduces its net bioavailability to 15%. With sustained administration of 400 mg twice daily, steady-state plasma concentrations of 84 to 167 ng/mL are reached in 7 days. The clearance is principally non-renal, with a terminal half-life of 24 hours. Dronedarone is a substrate for and a moderate inhibitor of CYP3A4. A potent CYP3A4 inhibitor may increase dronedarone exposure by as much as 25-fold. Consequently, dronedarone should not be coadministered with potent CYP3A4 inhibitors like antifungals, macrolide antibiotics, or protease inhibitors, verapamil and diltiazem. Concomitant administration of dronedarone and digoxin results in a 1.7- to 2.5-fold increase in serum digoxin concentration, likely due to a P-glycoprotein–mediated interaction in the kidney. Coadministration of dronedarone and simvastatin, a CYP3A4 substrate, leads to a 2- to 4-fold increase in simvastatin levels and the potential for statin-induced myopathy. Dronedarone is also a CYP2D6 inhibitor and causes a modest increase in bioavailability of metoprolol in CYP2D6 extensive metabolizers. Dronedarone, causes partial inhibition of tubular transport of creatinine, which leads to increase in serum creatinine concentration that is not related to reduced glomerular filtration. On the basis of its pivotal clinical trials, dronedarone can be administered only at doses of 400 mg twice daily. Adjustment in the prescribed amount, indicated by age, gender, race, renal function, tolerance, or the use of concomitant interacting drugs have not been studied and therefore cannot be recommended.
Conclusion. Dronedarone can be administered to reduce cardiovascular hospitalization in patients with AF or atrial flutter. Structural modification of dronedarone was introduced to shorten the half-life, decrease lipophilicity, and minimize noncardiovascular toxicity as compared to amiodarone.
Keywords:
Dronedarone,
pharmacokinetics,
Atrial Fibrillation,
Atrial Flutter
Conference:
8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010, Thessaloniki, Greece, 1 Oct - 5 Oct, 2010.
Presentation Type:
Poster
Topic:
Food, drugs and environmental xenobiotics
Citation:
Bostanitis
I and
Tsalidou
M
(2010). Pharmacokinetics of dronedarone.
Front. Pharmacol.
Conference Abstract:
8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010.
doi: 10.3389/conf.fphar.2010.60.00108
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Received:
28 Oct 2010;
Published Online:
04 Nov 2010.
*
Correspondence:
Dr. Ioannis Bostanitis, Aristotle University of Thessaloniki, Second Cardiology Department, Thessaloniki, Greece, bostangiannis@yahoo.gr