EP2280700A2

EP2280700A2 - Combination of dronedarone with at least one diuretic, and therapeutic use thereof

Info

Publication number: EP2280700A2
Application number: EP09738344A
Authority: EP
Inventors: Davide Radzik; Martin Van Eickels
Original assignee: Sanofi Aventis France
Current assignee: Sanofi SA
Priority date: 2008-04-17
Filing date: 2009-04-16
Publication date: 2011-02-09
Also published as: ECSP10010552A; CA2721560A1; US20110136899A1; IL208749A0; KR20110005245A; MA32355B1; SV2010003702A; AR071326A1; FR2930149B1; FR2930149A1; CO6300842A2; UY31772A; PE20091808A1; EA201071203A1; AU2009241966A1; MX2010011401A; CR11735A; WO2009133310A3; NI201000171A; DOP2010000308A

Abstract

The invention relates to a combination of dronedarone or one of the pharmaceutically acceptable salts thereof with at least one diuretic, and to the therapeutic use thereof.

Description

ASSOCIATION OF DRONEDARONE WITH AT LEAST ONE DIURETIC, ITS APPLICATION IN THERAPEUTICS.

The present invention relates to a combination of dronedarone or a pharmaceutically acceptable salt with at least one diuretic, its therapeutic application.

2-n-butyl-3- [4- (3-di-n-butylaminopropoxy) benzoyl] -5-methylsulfonamidobenzofuran or dronedarone and its pharmaceutically acceptable salts are described in European Patent EP 0471 609 B1.

Dronedarone blocks potassium, sodium and calcium channels and also has anti-adrenergic properties.

Dronedarone is an antiarrhythmic agent effective in maintaining sinus rhythm in patients with atrial fibrillation or atrial flutter.

The Applicant has surprisingly found that dronedarone significantly reduces cardiovascular hospitalizations and mortality in patients with a history of atrial fibrillation or atrial flutter due to its ability to modulate serum potassium. Indeed, patent applications WO98 / 40067 and WO97 / 34597 disclose the use of benzofuran derivatives for reducing post-infarction mortality in patients with reduced left ventricular function after myocardial infarction, without disturbing the rhythm requiring a antiarrhythmic treatment.

But these claims do not disclose or suggest the use of dronedarone to reduce cardiovascular hospitalizations and / or mortality in patients with a history of atrial fibrillation or atrial flutter due in part to its ability to modulate potassium levels in the body. blood.

Potassium is the main intracellular ion and plays a vital role in physiology.

Indeed, this ion is the main osmotically active intracellular ion and plays an important role in the regulation of intracellular volume.

A constant and stable potassium concentration is essential for the functioning of enzymatic systems as well as for good growth and cell division. Potassium contributes to the establishment of the resting potential of the cell membrane, therefore changes in potassium concentration, particularly in the extracellular compartment, have effects on cellular excitability in the nervous, muscular and cardiac systems. The decrease in potassium concentration is known to increase cardiac hyperexcitability at the ventricular level which can lead to serious, potentially fatal rhythm disturbances.

The deleterious role of decreasing potassium concentration has been documented in disparate clinical situations. For example, in patients with heart failure, a decrease in potassium concentration may lead to fatal rhythm disturbances, diuretic agents with a "potassium-sparing" effect have been shown to have a beneficial effect in this population.

The rapid decrease in potassium levels following abrupt cessation of intense physical activity may also be responsible for some sudden deaths.

A possible contribution of decreased potassium levels has been suggested in the sudden death of patients treated with antipsychotics as well as in acute alcohol withdrawal syndromes. Dietary habits with decreased potassium intake can lead to sudden death in susceptible subjects even without structural cardiac pathology.

The risk of fatal cardiac hyperexcitability is particularly important in patients who receive anti-arrhythmic therapy that extends the duration of cell repolarization such as sotalol (Sotalex®). These agents may indeed induce torsade de pointe, a severe and potentially fatal ventricular tachycardia. Torsades de pointes are facilitated by the decrease in potassium concentration.

Finally, it has been shown that the decrease in potassium concentration induces atrial fibrillations (Manoach M., J. Mol., Cardiol, 1998, 30 (6): A4 [8]).

Another clinical situation where the risk of potentially fatal cardiac arrhythmias is high is represented by patients treated with diuretics, these drugs widely prescribed in many indications, the most frequent being arterial hypertension but also heart failure, kidney failure, nephrotic syndrome, cirrhosis and glaucoma, are at risk of decreasing potassium levels, except for potassium-sparing diuretics.

The decrease in potassium concentration following diuretic therapy may be complicated by sudden death, particularly in patients with impaired contractile function of the heart or left ventricular dysfunction or after myocardial infarction.

Diuretics are widely prescribed for their effectiveness in treating a variety of conditions such as high blood pressure, congestive heart failure, kidney failure, nephrotic syndrome, cirrhosis, glaucoma.

One of the major consequences of diuretic therapy, except for potassium-sparing diuretics, is the increased excretion of potassium that may lead to hypokalemia. However, hypokalemia is known to increase cardiac excitability leading, in some patients, to ventricular arrhythmias and sudden deaths (Cooper et al., Circulation, 1999, 100, pages 1311-1315).

No association between an antiarrhythmic agent and a diuretic, to date, in therapeutics, has shown any effects on the regulation of potassium levels in the blood and in particular its impact in patients with a history of atrial fibrillation or atrial flutter.

The subject of the present invention is therefore also the use of a combination of dronedarone and its pharmaceutically acceptable salts with at least one diuretic, in particular a non-potassium sparing diuretic for the preparation of a medicinal product intended to regulate the level of potassium. in the blood, especially for the prevention of hypokalemia.

The subject of the present invention is also the use of a combination of dronedarone and its pharmaceutically acceptable salts with at least one diuretic, in particular a potassium-sparing diuretic, for the preparation of a medicinal product intended for the prevention of cardiovascular hospitalizations and / or mortality including cardiovascular mortality and more particularly sudden death in patients with a history of atrial fibrillation or flutter auricular especially by regulating the level of potassium in the blood and more particularly by preventing hypokalemia.

The subject of the present invention is therefore also a combination of dronedarone or a pharmaceutically acceptable salt with at least one diuretic, excluding furosemide, hydrochlorothiazide, metolazone, amiloride and spironolactone. and in particular a non-potassium sparing diuretic excluding furosemide, hydrochlorothiazide and metolazone.

Said diuretic is administered at therapeutically active doses chosen between 1 mg / day and 2 g / day.

Said association may be simultaneous, separate or sequential.

Among the pharmaceutically acceptable salts of dronedarone, mention may be made of the hydrochloride.

By non-potassium sparing diuretic is meant a diuretic increasing the excretion of potassium.

By cardiovascular hospitalization is meant a hospitalization resulting from at least one of the following pathologies (Hohnloser et al., Journal of Cardiovascular Electrophysiology, Jan. 2008, 19, No. 1, pages 69-73): relating to atherosclerosis - myocardial infarction or unstable angina,

- stable angina pectoris or atypical chest pain, syncope, transient ischemic attack or cerebrovascular accident (except intracranial hemorrhage), - atrial fibrillation and other disorders of supraventricular rhythm, non-fatal cardiac arrest, ventricular arrhythmia,

- cardiovascular surgery except cardiac transplantation, cardiac transplantation, - implantation of a pacemaker, implantable defibrillator (ICD) or other cardiac device, percutaneous coronary intervention, cerebrovascular or peripheral, changes in blood pressure (hypotension, hypertension, except syncope), cardiovascular infection, bleeding / major bleeding (requiring two or more red blood cells or any intracranial hemorrhage),

- pulmonary embolism or deep vein thrombosis, - worsening of congestive heart failure including acute pulmonary edema or cardiac dyspnea.

The term "mortality" covers mortality due to any cause, whether cardiovascular or non-cardiovascular or unknown.

The term "cardiovascular mortality" covers, in the context of the invention, mortality due to all cardiovascular causes (all deaths except those due to a non-cardiovascular cause) including death of arrhythmic origin also known as arrhythmic death, and more particularly, sudden death of cardiovascular origin, also called sudden death.

The term "sudden death" generally refers to death occurring within one hour or less of an hour after the onset of new symptoms or unexpected death without witnesses.

It should also be noted that the expression "having a history of atrial fibrillation or atrial flutter", "having atrial fibrillation or paroxysmal or persistent atrial flutter", "having a history / history of atrial fibrillation or atrial flutter or atrial fibrillation or atrial flutter "means a patient who has had in the past one or more episodes of atrial fibrillation or flutter and / or atrial fibrillation or atrial flutter at the time of use of the dronedarone or a pharmaceutically acceptable salt thereof. In particular, a patient who has had one or more episodes of atrial fibrillation or flutter in the past may have had these episodes at least three months or more before random assignment, for example, between three and six months.

Patients with a history of atrial fibrillation or atrial flutter may also include patients with at least one of the following risk factors:

- age equal to or greater than 70 years, more particularly equal to or greater than 75 years, - hypertension,

- diabetes,

- history of cerebrovascular accident or systemic embolism,

- left atrial diameter greater than or equal to 50 mm measured by echocardiography, - left ventricular ejection fraction less than 40% measured by two-dimensional ultrasound.

Patients with a history of atrial fibrillation or atrial flutter may also include patients with additional risk factors, namely at least one of the following conditions: hypertension, underlying structural heart disease, tachycardia, coronary artery disease, - non-rheumatic valve heart disease, dilated cardiomyopathy of ischemic origin, atrial fibrillation or flutter removal, eg by catheter or endomyocardial ablation, supraventricular tachycardia other than atrial fibrillation or flutter, - history of cardiac valve surgery,

- non-ischemic dilated cardiomyopathy hypertrophic cardiomyopathy, rheumatic heart disease,

- sustained ventricular tachycardia, - congenital heart disease, - Ablation for example by catheter for tachycardia other than for atrial fibrillation or flutter,

ventricular fibrillation, and / or at least one cardiac device chosen from: a pacemaker, an implantable defibrillator ("ICD").

By "regulating the level of potassium in the blood" is meant the prevention of the decrease or a possible increase of the said rate.

The main classes of non-potassium sparing diuretics are: thiazides, loop diuretics, proximal diuretics (osmotic, carbonic anhydrase inhibitors).

For their therapeutic use, dronedarone and its pharmaceutically acceptable salts are generally introduced into pharmaceutical compositions. These pharmaceutical compositions contain an effective dose of dronedarone or a pharmaceutically acceptable salt thereof, as well as at least one pharmaceutically acceptable excipient.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.

In said pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, dronedarone, or its salt, may be administered in unit dosage form. , in admixture with conventional pharmaceutical excipients, to animals and to humans in the cases mentioned above.

Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration , by inhalation, forms of topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants. For topical application, dronedarone and its pharmaceutically acceptable salts can be used in creams, gels, ointments or lotions.

For example, a unit dosage form of dronedarone or a pharmaceutically acceptable salt thereof in tablet form may correspond to one of the following examples:

Orally, the dose of dronedarone administered per day can be as high as 800 mg in one or more doses.

In particular, the dose of dronedarone administered may be taken with food.

In particular, the dose of dronedarone administered per day, orally, can be as high as 800 mg taken twice with a meal.

In particular, the dose of dronedarone administered daily, orally, may be taken at a frequency of twice a day with a meal for example with breakfast and dinner.

More particularly, both plugs can include the same amount.

There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the appropriate dosage for each patient is determined by the physician according to the mode of administration, the weight, the pathology, the body surface, the cardiac output and the response of said patient.

The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises administering to a patient an effective dose of dronedarone, or a pharmaceutically acceptable salt thereof.

The present invention is illustrated by the following data with reference to the accompanying drawings in which:

Figure 1 represents a Kaplan Meier curve with the cumulative rate of hospitalization or all-cause death over a 24-month period; Figure 2 shows a Kaplan Meier curve with the cumulative rate of hospitalization or cardiovascular death over a 30-month period;

Figure 3 represents a Kaplan Meier curve with the cumulative rate of hospitalization or sudden death over a 30-month period;

Figure 4 shows a Kaplan Meier curve with the cumulative rate of hospitalization over a 30-month period;

Figure 5 shows a Kaplan Meier curve with the cumulative rate of all-cause death over a 30-month period;

Figure 6 shows a Kaplan Meier curve with the cumulative rate of cardiovascular death over a 30-month period; Figure 7 shows a Kaplan Meier curve with the cumulative rate of sudden death over a 30-month period;

Figure 8 shows the average changes in potassium between the first and the last administration over a period of 30 months.

The efficacy of dronedarone and its pharmaceutically acceptable salts compared to placebo for the prevention of cardiovascular hospitalization or mortality was demonstrated by dronedarone hydrochloride in a prospective clinical study. , multinational, multi-centric and double-blind with random assignment into two treatment groups (dronedarone hydrochloride treated group and placebo treated group) of patients with a history of atrial fibrillation or atrial flutter.

I. Selection of patients Patients had a history of atrial fibrillation or flutter and / or could be in normal sinus rhythm or atrial fibrillation or flutter at baseline.

The recruitment of patients was carried out taking into account the following inclusion criteria:

Inclusion criteria:

1) One of the following risk factors should be present: age at or above age 70, or even above age 75, with or without at least one of the following risk factors: o hypertension (taking antihypertensive drugs at at least two different classes), o diabetes, history of stroke (transient ischemic attack or cerebrovascular accident) or systemic embolism, o left atrial diameter greater than or equal to 50 mm measured by echocardiography, o fraction of left ventricular ejection less than 40% measured by two-dimensional ultrasound,

2) Availability of an electrocardiogram performed in the last 6 months to document the presence or history of atrial fibrillation or flutter.

3) Availability of an electrocardiogram performed in the last 6 months to document the presence or absence of normal sinus rhythm.

II. Duration and treatment

The treatment was initiated from tablets containing either the placebo or a quantity of dronedarone hydrochloride corresponding to 400 mg of dronedarone one tablet in the morning during or shortly after breakfast and one tablet in the evening during or shortly after dinner.

The duration of the planned treatment was variable depending on the time of inclusion of each patient in the study and could range from 12 months minimum for the last patient included up to a maximum corresponding to the entire duration of the study (12 months + duration of inclusion) is about 30 months for the first patients included.

III. Results

The results obtained in this trial were analyzed by the Kaplan Meyer method for the figures and the relative risk (RR) was estimated using the proportional effect Cox model.

Relative risk (RR) is the ratio of the rates of occurrence of hospitalization or death in patients taking dronedarone compared to patients receiving placebo.

The percentage reduction x of a given event (hospitalization, death, cardiovascular death, etc.) is calculated as follows: x = 1 - relative risk.

III. 1. Results for Cardiovascular Hospitalizations and Mortality (Primary Endpoint)

Of the 4628 patients included in the study, 2301 were in the dronedarone hydrochloride group.

There were 917 events in the placebo group versus 734 in the dronedarone hydrochloride group.

The calculated relative risk is 0.758 with a p = 2.10 ⁸ , a reduction in cardiovascular hospitalizations and deaths of 24.2% in dronedarone hydrochloride, the result being highly significant.

Figure 1, which reproduces the results obtained, shows a clear separation of the two cumulative curves very early after the start of treatment, this separation persisting over time throughout the duration of the study. III. 2, Results for Cardiovascular Hospitalization and Cardiovascular Mortality

There were 892 events in the placebo group versus 701 in the dronedarone hydrochloride group.

The calculated relative risk is 0.745 with a p = 45.10 ¹⁰ , a reduction of cardiovascular hospitalizations and cardiovascular deaths of 25.5% under dronedarone hydrochloride, the result being highly significant.

Figure 2, which reproduces the results obtained, shows a clear separation of the two cumulative curves very early after the start of treatment, this separation persisting over time throughout the duration of the study.

III. 3. Results for Cardiovascular Hospitalizations and Sudden Death

Of the 4628 patients included in the study, 2301 were in the dronedarone hydrochloride group. There were 873 events in the placebo group versus 684 in the dronedarone hydrochloride group.

The calculated relative risk is 0.743 with a p = 48.10 ¹⁰ , a reduction of cardiovascular hospitalizations and sudden death of 25.5% in dronedarone hydrochloride, the result being highly significant.

Figure 3, which reproduces the results obtained, shows a clear separation of the two cumulative curves very early after the start of the treatment this separation persisting in time throughout the study.

III. 4. Results for cardiovascular hospitalizations

There were 859 events in the placebo group versus 675 in the dronedarone hydrochloride group. The calculated relative risk is 0.745 with a p = 9.10 ⁹ , a reduction of cardiovascular hospitalization of 25.5% in dronedarone hydrochloride.

Figure 4, which reproduces the results obtained, shows a clear separation of the two cumulative curves, very early after the start of the treatment, this separation persisting in time throughout the duration of the study.

III. 5. Results for all-cause mortality

There were 139 deaths in the placebo group compared to 116 in the dronedarone hydrochloride group.

The calculated relative risk is 0.844 with p = 0.1758, a reduction in cardiovascular hospitalizations of 15.6% in dronedarone hydrochloride.

Figure 5, which reproduces the results obtained, shows a clear separation of the two cumulative curves, very early after the beginning of the treatment, this separation persisting in time throughout the duration of the study.

111.6 Results relating to cardiovascular mortality.

There were 94 cardiovascular deaths in the placebo group compared to 65 in the dronedarone hydrochloride group.

The calculated relative risk is 0.698 with p = 0.0252, a reduction in cardiovascular mortality of 30.2% in dronedarone hydrochloride.

Figure 6, which reproduces the results obtained, shows a clear separation of the two cumulative curves, very early after the beginning of the treatment, this separation persisting in time during the entire duration of the study.

111.7 Results related to sudden death Of the 4628 patients included in the study, 2301 were in the dronedarone hydrochloride group.

There were 35 sudden deaths in the placebo group compared to 14 in the dronedarone hydrochloride group. The calculated relative risk is 0.405 with a p = 0.0031, a reduction in sudden death of 59.5% in dronedarone hydrochloride.

Figure 7, which reproduces the results obtained, shows a clear separation of the two cumulative curves, very early after the beginning of the treatment, this separation persisting in time during the entire duration of the study.

III.8 Regulation of serum potassium

The modulatory effect of potassium concentration is clearly documented in the study by the results of regular blood tests carried out throughout the duration of the study as part of the monitoring of vital parameters.

Potassium variations (in mmol / L) between the first and last administration of study drug are included in Figure 8 wherein B means basal level, J means day and M, month.

An analysis of the covariance of the change in serum potassium, taking into account the baseline value during study to 24 months, shows a significant difference in favor of dronedarone compared to placebo (p <0.0001).

The dronedarone thus makes it possible to regulate the level of potassium in the blood.

III.9. Results for patients in the study receiving a diuretic-based regimen

The clinical results of the study support the hypothesis that potassium modulation decreases the risk of sudden death, particularly in patients at risk of increased potassium exacerbation by diuretic therapy. Indeed, reducing the risk of sudden death by dronedarone is mean prevention of sudden death compared to placebo was approximately 70.4% in patients on diuretics and approximately 34% in patients without diuretics.

In addition, the risk reduction was greater in diuretic-sensitive patient groups such as hypertensives where the risk reduction was approximately 62% compared to a reduction of approximately 45.5% in non-hypertensive patients. hypertensive.

Claims

1. Use of a combination of dronedarone or a pharmaceutically acceptable salt thereof with at least one diuretic for the preparation of a medicament for the prevention of cardiovascular hospitalization and / or mortality, especially cardiovascular mortality, in patients having a history of atrial fibrillation or atrial flutter.

2. Use of a combination of dronedarone or a pharmaceutically acceptable salt thereof with at least one diuretic for the preparation of a medicament for regulating the level of potassium in the blood.

3. Use according to one of claims 1 or 2 characterized in that said at least one diuretic is a potassium non-sparing diuretic.

4. Use according to one of claims 2 or 3 for the preparation of a medicament for the prevention of hypokalemia.

5. Use according to one of the preceding claims, characterized in that the patients have, in addition, at least one of the following risk factors:

- hypertension,

- diabetes,

- history of cerebrovascular accident or systemic embolism,

- left atrial diameter greater than or equal to 50 mm measured by echocardiography,

- Left ventricular ejection fraction less than 40% measured by two-dimensional ultrasound.

6. Use according to one of the preceding claims, characterized in that the patients have, in addition, at least one of the following pathologies:

- hypertension, underlying structural heart disease,

- tachycardia,

- coronary heart disease, - non-rheumatic valve heart disease, dilated cardiomyopathy of ischemic origin, fibrillation ablation or atrial flutter by catheter,

- supraventricular tachycardia other than atrial fibrillation or flutter,

- history of valvular surgery, - nonischemic dilated cardiomyopathy

- hypertrophic cardiomyopathy, rheumatic heart disease,

- sustained ventricular tachycardia, congenital heart disease, - catheter ablation for tachycardia other than for atrial fibrillation or flutter,

ventricular fibrillation, and / or at least one cardiac device chosen from:

- a pacemaker, - an implantable defibrillator ("ICD").

7. Use according to one of the preceding claims characterized in that the dose of dronedarone administered per day orally may reach 800 mg / kg, in one or more doses.

8. Association of dronedarone or a pharmaceutically acceptable salt thereof with at least one diuretic, excluding furosemide, hydrochlorothiazide, metolazone, amiloride, spironolactone and mannitol.

9. Association according to claim 8, characterized in that said at least one diuretic is a potassium non-sparing diuretic, excluding furosemide, hydrochlorothiazide, metolazone and mannitol.