DESCRIPTION
Dronedarone is a derivated of Amiodarone. It is a Class III anti-arrhythmic drug wich doesn’t have tyroid toxicity, unlike Amiodarone. It is commercialized as Multaq©.
CHEMICAL STRUCTURE
Dronedarone is a non-iodinated benzofuran derivative of amiodarone. It is manufactured from amiodarone by the removal of iodine, the addition of a methyl sulfonamide group and the modification of the N-terminal region. The iodine part in particular is said to be responsible for thyroid toxicity. These modifications also aim to improve the molecule’s safety profile by decreasing its lipophilicity and distribution volume and by providing a shorter half life.
PHARMACOKINETICS
ABSORPTION
Following oral administration in fed condition, dronedarone is well absorbed (at least 70%). However due to presystemic first pass metabolism, the absolute bioavailability of dronedarone (given with food) is 15%. Concomitant intake of food increases dronedarone bioavailability by on average 2- to 4- fold. After oral administration in fed conditions, peak plasma concentrations of dronedarone and the main circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours. After repeated administration of 400 mg twice daily, steady state is reached within 4 to 8 days of treatment and the mean accumulation ratio for dronedarone ranges from 2.6 to 4.5. The steady state mean dronedarone Cmax is 84-147 ng/ml and the exposure of the main N-debutyl metabolite is similar to that of the parent compound. The pharmacokinetics of dronedarone and its N-debutyl metabolite both deviate moderately from dose proportionality: a 2-fold increase in dose results in an approximate 2.5- to 3.0-fold increase with respect to Cmax and AUC.
DISTRIBUTION
The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is 99.7% and 98.5% respectively and is not saturable. Both compounds bind mainly to albumin. After intravenous (IV) administration the volume of distribution at steady state (Vss) ranges from 1,200 to 1,400 l.
BIOTRANSFORMATION
Dronedarone is extensively metabolised, mainly by CYP3A4. The major metabolic pathway includes N-debutylation to form the main circulating active metabolite followed by oxidation, oxidative deamination to form the inactive propanoic acid metabolite, followed by oxidation, and direct oxidation. The N-debutyl metabolite exhibits pharmacodynamic activity but is 3 to 10-times less potent than dronedarone. This metabolite contributes to the pharmacological activity of dronedarone in humans. It is also a CYP2D6 inhibitor, and can inhibit P-glycoprotein transport.
ELIMINATION
After oral administration, approximately 6% of the labelled dose is excreted in urine mainly as
metabolites (no unchanged compound excreted in urine) and 84% are excreted in faeces mainly as metabolites. After IV administration the plasma clearance of dronedarone ranges from 130 to 150 l/h. The terminal elimination half-life of dronedarone is around 25-30 hours and that of its N-debutyl metabolite around 20-25 hours. In patients, dronedarone and its metabolite are completely eliminated from the plasma within 2 weeks after the end of a 400 mg twice daily- treatment.
EMA: Summary of product characteristics
MOLECULAR MECHANISM
Dronedarone is a multichannel blocker that meets criteria of all four Vaughan Williams antiarrhythmic drug classes:
- CLASS I: heart rate-dependent inhibition of the rapid Na+ current;
- CLASS II: α- and β-adrenergic receptor inhibition;
- CLASS III: blockade of K+ outward currents as the main mechanism of action;
- CLASS IV: blockade of slow Ca2+ inward currents.
Class I and III effects increase refractory periods and decelerate cardiac conduction, providing mechanisms that induce rhythm control. Although precise mechanisms of dronedarone action are not fully understood, balanced inhibition of multiple outward currents may explain the decrease in the transmural dispersion of repolarization, which prevents significant proarrhythmic effects.
Furthermore, in contrast to pure IK, dronedarone increases action potential duration and effective refractory period without reverse use-dependency, preventing the risk of early afterdepolarization.
In addition, class II and IV effects contribute to rate control properties as well as the anti-adrenergic (class II) and blood pressure lowering (class IV) effects of the drug.
Dronedarone as a new treatment option for atrial fibrillation patients: pharmacokinetics, pharmacodynamics and clinical practice
Dronedarone
Although Dronedarone has multiple mechanism of action, the main is the block of the K+ channels. It blocks the outward current of K+ causing the prolongation of repolarization and refractory period. This prevents re-entrant arrhythmias.
SIDE EFFECTS
Dronedarone side effect’s included bradycardia, QT-interval prolongation, diarrhea, nausea, rash, and an increase in the serum creatinine level.
The QT-interval prolungation is due from the block of potassium channel (hERG).
EFFECTS ON CREATININE
The increase in creatinine level may not reflect a deterioration in renal function. Dronedarone reduces renal creatinine clearance by about 18%, without evidence of an effect on glomerular filtration rate, apparently as a result of a specific partial inhibition of tubular organic-cation transporters.
In summary: small rise in the creatinine level was expected with dronedarone and did not necessarily indicate a decline in renal function.
TOXICITY
No significant increase in the rates of thyroid or pulmonary disorders was seen with dronedarone. This observation may suggest that dronedarone has a more benign side-effect profile than amiodarone and that the intended benefits of the modifications in the benzofuran chemical structure were achieved.
Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation
HEPATOTOXICITY
There have been reports of liver injury, including two cases of liver failure requiring transplantation in patients treated with dronedarone. Some of these cases occurred soon after the start of treatment.
For patients who are prescribed dronedarone, must be carried out liver function tests:
- Before therapy,
- On a monthly basis for six months,
- The 9 th and 12 th month and thereafter on a regular basis.
If the levels of alanine aminotransferase are elevated to ≥ 3 times the upper limit of normal (ULN), these levels should be re-tested within 48-72 hours. If ALT levels are confirmed to ≥ 3 x ULN after the re-measurement, treatment with dronedarone should be stopped.
Nota informativa AIFA
INTERACTIONS
Dronedarone has interactions with other drugs using the CYP450 systems and, thus, should not be administered with potent CYP3A4 inhibitors, including antifungals, certain oral macrolide antibiotics and protease inhibitors, because CYP3A4 inhibition may increase plasma levels of dronedarone and cause unwanted adverse effects.
However, dronedarone can be co-administered with moderate CYP3A4 inhibitors, such as verapamil and diltiazem, but with some caution (e.g. by using lower doses of drugs).
A p-glycoprotein-mediated interaction influences dronedarone - digoxin interaction and may result in increased serum digoxin levels and digitalis intoxication.
Dronedarone also interacts with commonly prescribed drugs, such as metoprolol and simvastatin. For example, dronedarone can increase serum simvastatin levels by 2- to 4-fold, and promote statin-induced myopathy. The interaction between dronedarone and metoprolol depends on CYP2D6 inhibition and results in an increased bioavailability of metoprolol.
| Drug | Enzyme Pathway | Effect | Dose Adjustment |
|---|
| Macrolide | CYP3A4 | Increased dronedarone exposure | Concomitant use is contraindicated |
| Antifungals | CYP3A4 | Increased dronedarone exposure | Concomitant use is contraindicated |
| Digoxin | p-glycoprotein | 2.5-fold increase in digoxin level | Halve the digoxin dose |
| Verapamil, Diltiazem | CYP3A4 (inhibitors) | 1.4- to 1.7-fold increase in dronedarone level | lower dose of calcium channel blocker |
| β-blockers | CYP2D6 (substrate) | 1.6-fold increase in metoprolol level | Lower β-blockers dose |
| Simvastatin | CP3A4 (substrate) | up to 4.0-fold increase in simvastatin level | Maximum simvastatin dose 20 Mg |
Dronedarone as a new treatment option for atrial fibrillation patients: pharmacokinetics, pharmacodynamics and clinical practice
Dronedarone is moderate inhibitor of CYP3A4 that has a role in both S and R warfarin metabolism. Unlike Amiodarone, Dronedarone increases S warfarin exposure by only 1.2-fold and does not cause clinically significant prolongation of INR values and excess risk of bleeding.
Dronedarone and vitamin K antagonists: A review of drug-drug interactions
Repeated doses of 300 ml of grapefruit juice three times daily resulted in a 3- fold increase in
dronedarone exposure. Therefore, patients should be warned to avoid grapefruit juice beverages while
taking dronedarone
INDICATIONS
Dronedarone is indicated to reduce risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter.
CONTROINDICATIONS
Not use in patient with:
- NYHA Class IV heart failure, or Class II-III with recent decompensation requiring hospitalization or referral to heart failure specialist
- Second or third degree AV block or SND without a pacemaker
- Concomitant use of strong CYP3A inhibitors (such as ketoconazole, itraconazole,voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir)
- Concomitant use of Q-T prolonging drugs or herbal products
- Baseline prolonged corrected QT interval (>500 msec) or PR interval (>280 msec)
- Severe hepatic failure
- Women who are pregnant or may become pregnant: Pregnancy and nursing are both considered contraindications to dronedarone. It may cause fetal harm and thus should be avoided during pregnancy or in those who may become pregnant. Furthermore dronedarone may pose potential harm in nursing infants. The safety and efficacy of dronedarone have not been proven in children below the age of 18 years.
Dronedarone: current evidence for its safety and efficacy in the management of atrial fibrillation
RELATIVE CONTROINDICATIONS
- New or worsening heart failure during treatment
- Hypokalemia or hypomagnesemia
- Corrected QT interval > 500 msec on dronedarone
COMPARISON OF PHARMACOLOGICAL AND CLINICAL CHARACTERISTICS OF DRONEDARONE AND AMIODARONE
| Characteristic | Amiodarone | Dronedarone |
|---|
| Iodine moiety | Yes | No |
| Half-life | 53 days | 14-30 h |
| Dosing | Daily after loading | Twice a day |
| Food Effect | Yes | Yes |
| CYP3A4 Metabolism | No | No |
| Inhibits tubular secretion of creatinine | Yes | Yes |
| Low torsades de pointes risk | Yes | Yes |
| Efficacy in suppressing AF | 65% | 50% |
| Efficacy in suppressing VT | Yes | Not yet studied |
| Decreases CV hospitalization | No | Yes |
| Reduces stroke risk | No | Yes |
| Warfarin interaction | Yes | No |
| Pulmonary/Thyroid Toxicity | Yes | No |
Dronedarone for the treatment of atrial fibrillation and atrial flutter: approval and efficacy
BIBLIOGRAPHY
AIFA - Nota informativa Gennaio 2011
EMA - Summary of product characteristic of Multaq
Goodman & Gilman's - The Pharmacological Basis of Therapeutics
PubMed
Wikipedia
Luca Amendolia e Luca Colombatti
