Bunidolol for cardioversion

Abstract

Disclosed are methods for cardioversion using bundanolol or a pharmaceutical composition comprising bundanolol for cardioversion of patients with paroxysmal or persistent AFib.

Description

[0001] This patent application is a divisional application of the patent application with application number 2024800516182, application date July 2, 2024, and invention title "Bunidalon for Cardiac Cardioversion".

[0002] Cross-references

[0003] This application claims the benefit of U.S. Non-Provisional Application No. 18 / 351,261, filed July 12, 2023, which in turn claims the benefit of U.S. Provisional Application No. 63 / 525,014, filed July 5, 2023, both of which are incorporated herein by reference in their entirety. Technical Field

[0004] This disclosure provides methods for cardioversion of the heart to sinus rhythm in patients with paroxysmal or persistent atrial fibrillation (AFib), methods using pharmaceutical compositions containing bunidarone.

[0005] Related applications

[0006] This application claims the benefit of U.S. Provisional Application No. 63 / 525,014, filed July 5, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0007] Patients with paroxysmal or persistent AFib and experiencing prolonged AFib episodes have a significantly increased risk of stroke and / or congestive heart failure. These risks increase with the duration of the episode. Symptomatic patients with paroxysmal or persistent AFib are significantly more likely to become aware of their condition, while asymptomatic patients wearing a heart rate monitor who trigger an alarm during a prolonged AFib episode become aware of their condition after the alarm is activated. In either case, many such patients who self-medicate to the hospital emergency room or intensive care unit due to a prolonged AFib episode are treated with cardioversion, which typically stops and restarts the heart to restore sinus rhythm. Currently, approximately 70,000 to possibly as many as 100,000 or more patients undergo cardioversion annually, and this number is increasing as the population ages. These figures represent a small fraction of patients who self-medicate to the emergency room for AFib. One study indicated that approximately 25% of AFib patients presenting to the emergency room received cardioversion. See Gulizia et al., Europace 2019;21(2): 230-238. This suggests that some untreated patients are contraindicated for the procedure due to comorbidities, and that some patients have sinus rhythm restored without cardioversion.

[0008] The preferred method for cardiac cardioversion is electrical cardioversion, which relies on stopping and restarting the heart to restore sinus rhythm. However, this procedure has several drawbacks. From the patient's perspective, there is a risk of death during or for several months after the procedure, such as due to a blood clot breaking off from the heart. From a clinician's perspective, electrical cardioversion requires the involvement of at least one or more nurses, anesthesiologists, and cardiologists, and necessitates the use of anticoagulants, all of which contribute to high costs for the healthcare system. From a cost perspective, cardiac cardioversion can cost thousands of dollars, and given the large number of cardioversions performed annually, this constitutes a significant cost burden on the healthcare system, especially when considering the costs associated with treating patients who have had blood clots break off during or shortly after the procedure. Summary of the Invention

[0009] This article discloses a method for cardioversion in patients with paroxysmal or persistent AFib with prolonged episodes, utilizing a single high dose of bunidarone or a pharmaceutically acceptable salt thereof to cardioversion to sinus rhythm. The single high dose of bunidarone or a pharmaceutically acceptable salt thereof is preferably administered orally, but other routes of administration, including intravenous, rectal, and pulmonary administration, are also considered. Patients undergoing cardioversion should first be considered suitable for this procedure.

[0010] In one embodiment, a method is provided for cardioversion in a patient with paroxysmal or persistent AFib who has prolonged episodes of AFib, the method comprising: a) assessing the patient to confirm that the patient has paroxysmal or persistent AFib and is suitable for cardioversion; b) administering bunidarone or a pharmaceutically acceptable salt thereof to the patient in an amount sufficient to cardioversion of the patient's AFib to sinus rhythm; and c) monitoring the patient after the administration to confirm that the patient responds to cardioversion.

[0011] In another embodiment, a method is provided for cardioversion of a patient with paroxysmal or persistent AFib who has prolonged episodes of AFib and is deemed suitable for cardioversion, the method comprising: a) administering bunidarone or a pharmaceutically acceptable salt thereof to the patient in an amount sufficient to achieve cardioversion of the AFib to a sinus rhythm, wherein the patient has been identified as having paroxysmal or persistent AFib and is deemed suitable for cardioversion; and b) monitoring the patient after the administration to confirm that the patient has responded to cardioversion.

[0012] Another embodiment provides a method for cardioversion in a patient with paroxysmal or persistent AFib who has prolonged episodes of AFib, the method comprising: a) administering an adequate amount of bunidarone or a pharmaceutically acceptable salt thereof to the patient to achieve a plasma concentration of at least about 13 ng / mL for a sustained period of time, thereby cardioversion of the patient's heart to sinus rhythm, wherein the patient has been identified as having paroxysmal or persistent AFib and is considered suitable for cardioversion; and b) monitoring the patient after the administration to confirm that the patient has responded to cardioversion.

[0013] In another embodiment, a method is provided for cardioversion in patients with prolonged AFib episodes who are considered suitable for cardioversion, the method comprising: a) Administer bunidarone or a pharmaceutically acceptable salt thereof to the patient in an amount sufficient to restore the AFib to sinus rhythm, wherein the patient has been confirmed to have paroxysmal or persistent AFib; and b) Monitor the patient after administration to confirm that the patient is responding to cardiac cardioversion.

[0014] Another embodiment provides a method for cardioversion in patients with paroxysmal or persistent AFib who experience prolonged AFib episodes, the method comprising: a) Administering an adequate amount of bunidarone or a pharmaceutically acceptable salt thereof to the patient to achieve a plasma concentration of at least about 13 ng / mL for a sustained period, thereby restoring the patient's heart to sinus rhythm, wherein the patient has been identified as having paroxysmal or persistent AFIb and is considered suitable for cardioversion; and b) Monitor the patient after administration to confirm that the patient is responding to cardiac cardioversion.

[0015] In one embodiment, the amount of bunidarone or a pharmaceutically acceptable salt thereof administered to the patient is sufficient to provide a sustained plasma concentration of at least about 13 ng / mL for at least about 3 hours, at least about 4 hours, at least about 5 hours, or at least about 6 hours after administration of bunidarone or a pharmaceutically acceptable salt thereof. Throughout the period during which the plasma concentration of bunidarone or a pharmaceutically acceptable salt thereof is maintained at about 13 ng / mL, continuous monitoring of the patient's heart rhythm is preferred. In a preferred embodiment, the plasma concentration of bunidarone or a pharmaceutically acceptable salt thereof ranges from about 13 ng / mL to up to about 350 ng / mL. max In another preferred embodiment, the plasma concentration of bunidarone or a pharmaceutically acceptable salt thereof ranges from about 50 ng / mL to about 350 ng / mL, and any subrange of about 10 ng within said range.

[0016] In one embodiment, bunidarone or a pharmaceutically acceptable salt thereof is administered orally, sublingually, intravenously (IV), rectally, as an aerosol (to the lungs), or via nasal spray, or a combination thereof. In a preferred embodiment, bunidarone or a pharmaceutically acceptable salt thereof is administered orally using capsules, pills, or tablets. Considering delivery efficiency, the amount required to achieve the plasma levels described above or herein may be lower when bunidarone or a pharmaceutically acceptable salt thereof is administered intravenously, sublingually, or via spray than the dose required for oral administration.

[0017] Based on the foregoing, the method described herein comprises administering bunidarone or a pharmaceutically acceptable saline thereof to a patient in an amount sufficient to restore AFib to sinus rhythm while maintaining plasma concentrations of bunidarone or a pharmaceutically acceptable saline thereof above the levels defined herein. In most cases, responsive patients are expected to achieve cardiac cardioversion within approximately 90 minutes, preferably approximately 60 minutes, more preferably approximately 45 minutes, or approximately 30 minutes following administration of bunidarone or a pharmaceutically acceptable saline thereof.

[0018] Typically, bunidarone or its pharmaceutically acceptable salts are used to reorient the heart in a single oral dose of about 400 mg to about 1,200 mg, and preferably about 800 mg to 1,200 mg. Preferably, each of these doses of bunidarone or its pharmaceutically acceptable salts is administered in the form of a single pill or a single capsule. In a preferred embodiment, the clinician selects the dose of bunidarone or its pharmaceutically acceptable salts to achieve a C60 concentration of at least about 50 ng / mL or higher based on its half-life data. maxThis treatment aims to maintain a therapeutic plasma concentration of bunidarone at least about 13 ng / mL in the patient for about 6 hours. For long-term maintenance of this therapeutic concentration, preferred doses of bunidarone or a pharmaceutically acceptable salt thereof include a single dose of 800 mg, 1,000 mg, or 1,200 mg, or any dose between said 800 mg and 1,200 mg. The dose of bunidarone or a pharmaceutically acceptable salt thereof may also be increased in increments of about 50 mg or about 100 mg between 400 mg and 1,200 mg (e.g., 1,100 mg or 700 mg). Sublingual, intravenous, rectal, and spray formulations of bunidarone should be less than 1,200 mg and expected to be about 10% to about 50% of the 1,200 mg dose used orally. On the other hand, consider administering bunidarone or its pharmaceutically acceptable salts to the patient via one or more methods, such as via IV and oral, sublingual and oral, sublingual and spray, oral and spray, oral and IV, IV and spray, or IV and sublingual administration. Intravenous administration is expected to induce a more rapid conversion to sinus rhythm in patients requiring it.

[0019] In one implementation, a second medication, such as a blood thinner (e.g., dabigatran, edoxaban, apixaban, or rivaroxaban-Xarelto), is administered concurrently with the administration of bunidarone or a pharmaceutically acceptable salt thereof. ® ).

[0020] It also provides the use of bunidarone or its pharmaceutically acceptable salts in the cardioversion of patients with paroxysmal or persistent AFib who have prolonged AFib episodes.

[0021] Another implementation provides the administration of a dose of bunidarone or a pharmaceutically acceptable salt thereof to a patient requiring cardioversion and identified as having paroxysmal or persistent AFib, the dose being sufficient to produce an effective plasma level of >50 ng / ml in the patient within 60 minutes of administration and to maintain the plasma level in the patient at >50 ng / ml for up to 6 hours, thereby converting a single prolonged PAF episode, a prolonged PAF storm, or a persistent AFib episode into a normal sinus rhythm in the patient.

[0022] Another implementation provides the use of bunidarone or a pharmaceutically acceptable salt thereof in cardioversion of patients with paroxysmal or persistent AFib who have prolonged AFib episodes.

[0023] Another embodiment provides an oral dose of bunidarone or a pharmaceutically acceptable salt thereof for cardioversion in patients with paroxysmal or persistent AFib episodes, the oral dose of bunidarone or a pharmaceutically acceptable salt thereof comprising about 1,000 mg to about 2,000 mg. The oral dose of bunidarone or a pharmaceutically acceptable salt thereof may be delivered in the form of a single bolus dose of about 1,000 mg, about 1,100 mg, about 1,200 mg, about 1,300 mg, about 1,400 mg, about 1,500 mg, about 1,600 mg, about 1,700 mg, about 1,800 mg, about 1,900 mg, or about 2,000 mg, and may be in any number of 50 mg increments between 1,000 mg and about 2,000 mg. As described in this paragraph, the dosage form of 1,000 mg to about 2,000 mg of bunidarone or a pharmaceutically acceptable salt thereof may be pills, tablets or capsules.

[0024] In another embodiment, a pharmaceutically acceptable salt of bunidarone is bunidarone tartrate. Attached Figure Description

[0025] This patent or application contains at least one color drawing. In accordance with 37 CFR § 1.84, the Patent Office will provide a color drawing copy of the published text of this patent or application upon request and payment of the necessary fees.

[0026] Figure 1 The study demonstrates the changes in plasma concentrations over time after different single doses of bunidarone. Data show that each single dose of 400 mg and above achieved a Cg greater than 50 ng / mL. max Furthermore, each dose maintained a concentration greater than approximately 13 ng / mL for more than 6 hours.

[0027] Figure 2 This study demonstrates a comparison of plasma bunidarone concentrations between fasting and eating patients. Detailed Implementation

[0028] This disclosure relates to a method for carding AFib to sinus rhythm in patients with paroxysmal or persistent atrial fibrillation (AFib) and in a prolonged period of AFib. The methods described herein use bunidarone to cardiolate the hearts of these patients. Undefined terms are given a definition in the context or as they are medically acceptable.

[0029] The terminology used herein is for the purpose of describing a particular implementation and is not intended to be limiting. Unless the context clearly indicates otherwise, the singular forms “a” and “the” used herein also include their plural forms.

[0030] definition

[0031] As used herein, the terms “optional” or “optionally” indicate that the event or situation subsequently described may or may not occur, and the description includes both the possibility that the event or situation will occur and the possibility that it will not occur.

[0032] As used herein, the term “about” used before numerical values ​​(e.g., temperature, time, quantity, concentration, etc., including ranges) indicates an approximate value that may vary within a range of (+) or (-) 15%, 10%, 5%, 1%, or any subrange and / or value between these values. Preferably, when the term “about” is used with respect to a dose, it indicates that the dose may vary by + / - 10%.

[0033] As used herein, the term "comprising" means that the composition or method includes the listed elements, but does not exclude other elements.

[0034] As used herein, the term "consistently of" when used to define compositions and methods should exclude other elements that are essential to the purpose of the composition. Therefore, a composition consisting primarily of the elements defined herein, or a method consisting primarily of the schemes defined herein, does not exclude other components that will not materially affect the essential and novel features of the claimed subject matter.

[0035] As used herein, the term "composed of" should refer to the absence of other ingredients or substantial method steps beyond trace levels. Embodiments defined by each of these transitional terms are within the scope of this disclosure.

[0036] As used herein, the term “AFib” or “atrial fibrillation” refers to all types of atrial fibrillation except for permanent AFib. These types include, but are not limited to, paroxysmal AFib, persistent AFib, and paroxysmal and persistent AFib with low (2 or less) and high (3 or more) CHA2DS2-VASc scores. The CHA2DS2-VASc score, representing congestive heart failure (C – 1 point), hypertension (H – 1 point), age ≥75 years (A – 2 points), diabetes (D – 1 point), stroke (S – 2 points), vascular disease (V – 1 point), age 65 to 74 years (A – 1 point), and sex (female Sc – 1 point), is a clinical predictive rule for assessing stroke risk in patients with non-rheumatic atrial fibrillation (AF). As mentioned above, each component risk factor accounts for 1 or 2 points in the CHA2DS2-VASc score.

[0037] As used herein, “long-duration AFib” refers to the length of time an AFib episode lasts. This length is associated with the risk of stroke and / or heart failure. Clearly, the longer the duration of an AFib episode, the higher the risk. Therefore, in one implementation, long-duration AFib refers to any AFib episode lasting at least approximately 30 minutes, or at least approximately 1 hour, or at least 5 hours, provided the patient has not been diagnosed with permanent AFib.

[0038] As used in this article, the term "paroxysmal AFib" refers to occasional and intermittent episodes of AFib lasting no more than 7 days, followed by a return to sinus rhythm. Often (but not always), patients with mild AFib are also classified as having paroxysmal AFib.

[0039] As used in this article, the term “persistent AFib” refers to occasional and intermittent AFib episodes that last for more than 7 days and may not be able to return to sinus rhythm without medical intervention (e.g., cardioversion).

[0040] As used herein, the term "bennydalone" refers to 2-(3-(4-(2-(diethylamino)ethoxy)-3,5-diiodobenzoyl)benzofuran-2-yl)acetic acid (S)-sec-butyl ester and its pharmaceutically acceptable salts. In some cases, bennydalone tartrate is also referred to as ATI-2042 or simply "2042". Bennydalone, as a free base, is represented by the following chemical formula: .

[0041] The term "bunidarone" includes pharmaceutically acceptable salts of its free base and encompasses all approved pharmaceutically acceptable salts. Acceptable salts of bunidarone include bunidarone tartrate or bunidarone citrate. In one embodiment, the pharmaceutically acceptable salt may be a polycarboxylate. As is known in the art, the salt dissociates from the free base in vivo. Furthermore, the major metabolite of bunidarone is a deacylated compound—a free acid. Therefore, when calculating the serum plasma concentration of bunidarone, the molecular weights of the free acid and free base are used to determine the molar concentration and concentration. Additionally, when administering salts other than tartrate, the dosage of bunidarone tartrate used herein must be adjusted accordingly to reflect the molecular weight variation due to the different salts.

[0042] Bunidarone has a complex mechanism of action and has been shown to reduce prolonged AFib episodes without significantly prolonging the QT interval. Bunidarone is designed to act on cardiac ion channels in a similar manner to amiodarone, but enhances late-stage Na+ ionization. + Channel blocking effect. Bunidarone has a deliberately modified metabolic pathway that results in a much shorter half-life than amiodarone, thus avoiding the accumulation-related toxicity commonly associated with amiodarone, and is completely inactivated and cleared from the body within hours to days after discontinuation.

[0043] As used herein, “single high dose” refers to a dose range of about 400 mg to about 1,200 mg of bunidarone, administered in one or more dose units or in a dosage form sufficient to achieve a bunidarone concentration of at least about 13 ng / mL in a patient requiring this dose. As noted above, when administered by inhalation, sublingual or intravenous administration, a dosage form sufficient to achieve a bunidarone concentration of at least about 13 ng / mL in a patient requiring this dose may be less than about 1,200 mg, while when administered orally, it may be more. When using the term “high dose,” combinations of these administration methods may be considered and employed. When using multiple dose units, they may be administered simultaneously with other units so that the entire dose is administered within about 30 minutes, and preferably within about 10 minutes. It should also be noted that when ingesting a high dose of bunidarone, the patient may be asked to eat food, which may be and preferably a high-fat food, to facilitate faster entry of the drug into the body system.

[0044] As used in this article, "C" max "This refers to the maximum plasma concentration of bunidarone after a single dose is administered to a patient."

[0045] As used in this article, “suitable patient” or “patient” means a person who has experienced paroxysmal or persistent AFIb for approximately 6 hours or less, or a person who has experienced paroxysmal or persistent AFIb but is determined to be thrombotic-free by transesophageal echocardiography or other means, or a person who is known to have persistent or paroxysmal AFIb and is taking blood thinners.

[0046] Methodology

[0047] The methods described herein use a single high-dose or large-dose administration of bunidarone to restore sinus rhythm in patients with prolonged AFib. These methods are suitable for patients diagnosed with paroxysmal or persistent AFib. Patients with permanent AFib do not respond to bunidarone and should be weaned off the drug by their attending physician. For patients diagnosed with paroxysmal or persistent AFib, or those with prolonged AFib who self-medicate and seek treatment at the emergency room or other medical facility capable of providing adequate care, clinicians or caregivers must confirm that the arrhythmia is AFib and not another known arrhythmia, and must also confirm that the patient is suitable for cardioversion.

[0048] Once confirmed, the attending physician administers a single high-dose dose of bunidarone to the patient. The administered dose should be sufficient to maintain a plasma concentration of bunidarone at at least about 13 ng / mL for at least about 3 hours, preferably at least about 4 hours, or at least about 5 hours, or at least about 6 hours. In a preferred embodiment, the dose range of bunidarone administered to the patient includes a single high-dose dose of about 800 mg, or at least about 1,000 mg, or at least about 1,200 mg. In some embodiments, a high single dose of bunidarone is used to rapidly achieve therapeutic concentrations in the body. When used in this manner, such doses will achieve plasma concentrations reaching C0.05. max The concentration is approximately 350 ng / mL or less, and will be maintained at at least approximately 40 ng / mL or approximately 50 ng / mL for approximately 5+ hours, or in some cases at least approximately 6 hours (see [link to relevant documentation]). Figure 1 In any case, such high dose levels ensured that plasma concentrations remained above approximately 13 ng / mL for up to approximately 6 hours, and in fact above approximately 40 ng / mL.

[0049] Once a large dose of bunidarone has been administered, the patient should be observed in the emergency room, ward, or other emergency care facility with heart rhythm monitored for a sufficient period to determine if the patient is responding to bunidarone. Once sinus rhythm is restored and plasma bunidarone concentrations decrease to a level deemed satisfactory by the attending physician, the patient may be discharged, provided there are no other complications requiring further observation. In a preferred embodiment, this level is below about 20 ng / mL, and preferably below about 15 ng / mL. In a preferred embodiment, the patient requires short-term observation (e.g., from about 30 minutes to about 6 hours) to ensure maintenance of sinus rhythm.

[0050] For patients who respond to the method, they can be discharged and wear a wearable device that records and optionally transmits heart rhythm data to determine the extent and duration of AFib. For patients who do not respond to the method, they can be treated with electrical cardioversion.

[0051] Pharmaceutical Composition

[0052] Bunidarone can be administered via a variety of recognized modes of administration, including oral, intravenous, rectal, and pulmonary delivery. Pharmaceutical compositions compatible with each of these delivery methods, and methods of delivery for such purposes, are well known in the art. Preferably, oral delivery is typically achieved using tablets, pills, capsules, etc. The specific form used for oral delivery is not critical.

[0053] Pharmaceutical dosage forms of bunidarone can be manufactured by any method well known in the art, such as conventional mixing, tableting, encapsulation, etc. The compositions disclosed herein may contain one or more physiologically acceptable inert components that facilitate the processing of the active molecule into a pharmaceutical formulation.

[0054] The composition may comprise a combination of a drug and at least one pharmaceutically acceptable excipient. An acceptable excipient is non-toxic, facilitates administration, and does not adversely affect the therapeutic effect of the claimed compound. Such excipients may be any solid, liquid, or semi-solid that is generally available to those skilled in the art.

[0055] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, and skim milk powder. Other suitable pharmaceutical excipients and their formulations can be found in *Remington Pharmaceutical Science*, edited by EW Martin (Mack Publishing Company, 18th edition, 1990).

[0056] The compositions disclosed herein may be provided as needed in single-use packaging. This packaging may, for example, comprise metal or plastic foil, such as blister packs, vials, or any other type of container. The packaging or dispensing device may be accompanied by application instructions, including, for example, instructions for use.

[0057] The amount of drug in the formulation may vary depending on the number of subunits required for daily or periodic drug dosage. Typically, based on a weight percentage (wt.%) of the total formulation, the formulation contains about 10 wt.% to 99 wt.% of the drug, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 20 wt.% to 70 wt.%.

[0058] Example

[0059] This disclosure can be further understood by referring to the following embodiments, which are for illustrative purposes only. The scope of this disclosure is not limited to the exemplary embodiments, which are only used to illustrate a single aspect of this disclosure. Any functionally equivalent methods are within the scope of this disclosure. In addition to what has been described herein, various modifications to the invention will be apparent to those skilled in the art based on the foregoing description and drawings, and these modifications are all within the scope of the appended claims. In these embodiments, the following terms are used herein, and they have the following meanings. Undefined abbreviations have their conventional medical meanings.

[0060] Note that the bunidarone concentrations used in the examples below include both free acid and free base forms of bunidarone.

[0061] The following abbreviations used in this document have the following meanings. Undefined abbreviations have their general meanings:

[0062] Example 1 – Determining the minimum concentration of bunidarone to shorten the duration of AFib attacks

[0063] In this embodiment, patients were selected with paroxysmal or persistent AFib and prolonged episode duration. Each patient had a pacemaker implanted to monitor their heart rate. Disease progression was then assessed by monitoring the patient's heart rhythm without bunidarone treatment, thereby generating a baseline level for AFib episode duration. Baseline data was collected over two weeks. Patients were then given bunidarone in escalating doses: 200 mg twice daily (bid); 400 mg twice daily (bid); 600 mg twice daily (bid); and 800 mg twice daily (bid), each dose maintained for two weeks, for a total of four treatment cycles. After completing the 800 mg twice daily (bid) treatment cycle, a two-week washout period was employed, whereby the washout period refers to the time following the last treatment to avoid misinterpretation of study-relevant observations that might be due to prior treatment. Pacemaker data were downloaded on days 8 and 14 of each two-week cycle, and the average for each test cycle is shown. Blood samples were drawn during each cycle, and bunidarone concentrations were measured. The results of this measurement are as follows:

[0064] Note: For the duration of AFib at all dosing levels from 400 mg bid to 800 mg bid, the maximum duration of AFib levels was less than 90 minutes, in fact less than 60 minutes and less than 45 minutes. At 600 mg bid, the longest average duration of AFib was 6 minutes (less than 30 minutes). It is also noted that the trough concentration Pk level of bunidarone was based on dosing intervals of approximately 12 hours and was not related to the trough concentration level 6 hours after administration.

[0065] This data supports the following premise: administration of high doses of bunidarone will rapidly achieve a C50 level of at least 50 ng / mL. max Plasma concentrations were maintained for a sufficient period of time to achieve cardioversion of AFib to sinus rhythm in patients. It was also noted that bunidarone was rapidly cleared from the blood, resulting in a plasma trough concentration of only 0.3 ng / mL two weeks after twice-daily administration of 800 mg bunidarone, or approximately 1.5% of the trough concentration of 19.8 ng / mL bunidarone at the twice-daily 800 mg dose, indicating rapid drug elution upon discontinuation.

[0066] Example 2 – Determining the change in plasma bunidarone concentration over time using different doses of the drug

[0067] In this embodiment, the plasma concentrations of bunidarone after using different single doses were evaluated. Specifically, as... Figure 1As shown, bunidarone was administered to patients in single doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1000 mg. Blood samples were drawn from each patient, and the concentrations of bunidarone or its inactive deacylated metabolites were measured. The obtained data were plotted in graphs, with each concentration corresponding to the C-value for the dose used. max And the trough value at 6 hours.

[0068] Specifically, Figure 1 Studies have shown that a single dose (or single oral dose) of 400 mg or more of bunidarone can provide a C60 concentration greater than 50 ng / mL within 60 minutes of administration. max Each dose maintained a plasma concentration greater than approximately 13 ng / mL for more than 6 hours. Furthermore, a single dose of 800 mg or 1,000 mg of bunidarone provided a plasma concentration of approximately 50 ng / mL at 6 hours and maintained at at least approximately 15 ng / mL at 8 hours.

[0069] Data also indicate that the use of high doses (e.g., 1,000 mg) of bunidarone can rapidly raise plasma C levels to over 300 ng / mL. max The concentration is rapidly reduced and eliminated to below approximately 20 ng / mL within about 8 hours. In summary, this rapid uptake and short-term clearance characteristic makes this high dose suitable for cardiac cardioversion, as high doses of bunidarone rapidly reach effective levels in the body within 60 minutes of administration and maintain plasma levels above approximately 13 ng / mL for at least 6 hours, followed by rapid elimination from the body. Overall, these data suggest that bunidarone can rapidly convert prolonged AFib episodes to significantly shorter episodes or eliminate AFib within 90 minutes or less after administration, thereby restoring the patient's heart to sinus rhythm.

[0070] Since bunidarone has been proven safe for in vivo administration in clinical studies, the use of bunidarone for cardiac cardioversion is an alternative to electrical cardioversion and related issues.

[0071] Example 3 – Effect of food on brunidaron concentration

[0072] This embodiment evaluated the effect of fasting or eating status on bunidarone plasma concentrations in patients. In this embodiment, patients were either fasting or eating before bunidarone administration. After bunidarone administration, blood was drawn from the patients, and the plasma concentration of bunidarone was measured. Figure 2 It was shown that at the same dose of brenidaron, C max The values ​​indicate that bunidarone absorption is increased. However, it should be noted that the C values ​​in the dietary group patients... max The time of occurrence was earlier than that of fasting patients (C).max The delay is approximately one hour. This suggests that for fasting patients about to undergo bunidarone cardioversion, it is preferable to eat approximately one hour (about 60 minutes) before the start of the cardioversion. These data show that, regardless of whether the drug is taken with food, a single oral dose of 400-1,000 mg can achieve an effective plasma concentration level of >50 ng / mL within 60 minutes and maintain that level, or even higher levels, for up to 6 hours, thereby converting a single long-duration PAF (paroxysmal atrial fibrillation) or persistent atrial fibrillation, or a prolonged AFIb storm that causes symptoms and leads to emergency room visits, into a normal sinus rhythm.

[0073] Implementation Plan

[0074] The following implementation schemes were considered.

[0075] [1] A method for cardioversion in a patient with paroxysmal or persistent AFib who has prolonged episodes of AFib and is deemed suitable for cardioversion, the method comprising: a) administering bunidarone or a pharmaceutically acceptable salt thereof to the patient in an amount sufficient to achieve cardioversion of the AFib to a sinus rhythm, wherein the patient has been confirmed to have paroxysmal or persistent AFib; and b) monitoring the patient after the administration to confirm that the patient has responded to cardioversion.

[0076] [2] A method for cardioversion in a patient with paroxysmal or persistent AFib who has prolonged episodes of AFib, the method comprising: a) administering an adequate amount of bunidarone or a pharmaceutically acceptable salt thereof to the patient to achieve a plasma concentration of at least about 13 ng / mL for a sustained period of time, thereby cardioversion of the patient’s heart to sinus rhythm, wherein the patient has been identified as having paroxysmal or persistent AFib and is considered suitable for cardioversion; and b) monitoring the patient after the administration to confirm that the patient has responded to cardioversion.

[0077] [3] The method according to any one of embodiments [1] or [2], wherein the amount of bunidarone or a salt thereof administered to the patient is sufficient to give the patient a plasma concentration of about 13 ng / mL to about 350 ng / mL, provided that the plasma concentration of bunidarone remains greater than 13 ng / mL for at least 6 hours after administration.

[0078] [4] The method according to any one of embodiments [1] or [3], wherein the amount of bunidarone or a salt thereof administered to the patient is sufficient to cause a plasma concentration of bunidarone or a salt thereof in the patient to be about 50 ng / mL to about 350 ng / mL for at least about 5 hours after administration.

[0079] [5] The method according to embodiment [4], wherein the amount of bunidarone or a salt thereof administered to the patient is sufficient to cause the plasma concentration of bunidarone or a salt thereof in the patient to reach about 50 ng / mL to about 350 ng / mL for at least about 6 hours.

[0080] [6] The method according to any one of the embodiments [1] to [5], wherein the bunidarone or its salt is administered orally, sublingually, intravenously, rectally or by aerosol.

[0081] [7] The method according to any one of the embodiments [1] to [6], wherein bunidarone or its salt is administered orally using capsules, pills or tablets.

[0082] [8] The method according to any one of embodiments [1] to [7], wherein the dose of said bunidarone or its salt is administered in a single dose of about 400 mg to about 2,000 mg.

[0083] [9] The method according to embodiment [8], wherein the dose of said bunidarone or its salt is administered in a single dose of about 800 mg to about 1,200 mg.

[0084]

[10] The method according to embodiment [8], wherein the dose of said bunidarone or salt thereof is administered in a single dose of about 1,000 mg.

[0085]

[11] The method according to embodiment [8], wherein the dose of said bunidarone or its salt is administered in a single dose of about 1,200 mg.

[0086]

[12] The method according to any one of embodiments [1] to

[11] further includes administering to the patient a blood thinner in combination with bunidarone or a salt thereof, wherein the blood thinner is dabigatran, edoxaban, apixaban or rivaroxaban.

[0087]

[13] The method according to any one of the embodiments [1] to

[12] , wherein the patient completes cardiac reversion approximately 90 minutes or less after administration of bunidarone or its salt.

[0088]

[14] The method according to any one of the embodiments [1] to

[12] , wherein cardioversion is completed about 60 minutes or less after administration of bunidarone or its salt.

[0089]

[15] The method according to any one of the embodiments [1] to

[12] , wherein cardioversion is completed about 45 minutes or less after administration of bunidarone or its salt.

[0090]

[16] The method according to any one of the embodiments [1] to

[12] , wherein cardioversion is completed about 30 minutes or less after administration of bunidarone or its salt.

[0091]

[17] The method according to any one of the embodiments [1] to

[12] , wherein the patient eats about 1 hour or less before administering bunidarone or its salt.

[0092]

[18] A combination kit comprising a single dose of bunidarone or a pharmaceutically effective salt thereof capable of cardioversion in a patient, and instructions for monitoring the patient after administration.

[0093]

[19] A dose of bunidarone or a pharmaceutically acceptable salt thereof is administered to cardioversion in a patient identified as having paroxysmal or persistent AFib, wherein the administered dose is sufficient to produce an effective plasma level of >50 ng / ml in the patient within about 60 minutes of administration and to maintain the plasma level of >50 ng / ml in the patient for up to about 6 hours, thereby cardioversion of the patient’s single prolonged PAF episode, prolonged PAF storm or persistent AFib episode to normal sinus rhythm.

[0094]

[20] Use of bunidarone or a pharmaceutically acceptable salt thereof for cardioversion in patients with paroxysmal or persistent AFib episodes, which is achieved by administering a dose of bunidarone according to any one of the embodiments [1]-

[19] .

[0095]

[21] An oral dose of bunidarone or a pharmaceutically acceptable salt thereof, as described in embodiment

[20] , comprising about 1,000 mg to about 2,000 mg in a single dose unit.

[0096]

[22] The oral dose of bunidarone or a pharmaceutically acceptable salt thereof as described in embodiment

[20] contains about 900 mg, about 1,000 mg, about 1,100 mg or about 1,200 mg in a single dose unit.

[0097]

[23] An oral dose of bunidarone according to any one of the embodiments

[21] to

[22] , wherein the dose unit is a pill, capsule or tablet.

[0098]

[24] An oral dose of bunidarone or a pharmaceutically acceptable salt according to any one of embodiments

[20] to

[23] , wherein the salt of bunidarone is bunidarone tartrate.

Claims

1. A method for performing cardiac cardioversion on a patient with prolonged episodes of paroxysmal or persistent AFib who is deemed suitable for cardioversion, the method comprising: a) Administering a single oral dose of bunidarone or a pharmaceutically acceptable salt thereof to the patient in an amount of about 900 mg to about 2,000 mg, wherein the amount is sufficient to achieve a peak plasma concentration of bunidarone of at least about 50 ng / mL in the patient and maintain a plasma concentration of bunidarone of at least about 13 ng / mL in the patient for at least 6 hours, wherein the patient's AFib heart rate cardioversion is sinus rhythm; and b) Monitor the patient’s heart rhythm after administration until the measured bunidarone plasma concentration is below about 20 ng / mL.

2. A method for inducing cardiac cardioversion in a patient diagnosed with paroxysmal or persistent AFib and currently in an AFib episode, the method comprising: a) Based on determining that the patient is suitable for cardioversion, administering to the patient a single oral dose of about 900 mg to about 2,000 mg of bunidarone or a pharmaceutically acceptable salt thereof to achieve a plasma concentration of at least about 13 ng / mL of bunidarone over a period of at least 6 hours, wherein the single oral dose comprises one or more units and is administered over a 30-minute time period; and wherein the step of determining that the patient is suitable for cardioversion includes determining one or more of the following: The patient was experiencing an AFib episode that was considered suitable for cardioversion. Data confirms that the patient did not have any blood clots; or The patient is receiving anticoagulant therapy. and b) Monitor the patient after administration to confirm that the patient is responding to and maintaining cardioversion.

3. The method of claim 2, wherein the amount of bunidarone or a pharmaceutically acceptable salt thereof in the single oral dose is sufficient to achieve a peak plasma concentration of bunidarone in the patient of at least about 300 ng / mL.

4. The method of claim 3, wherein the amount of bunidarone or a pharmaceutically acceptable salt thereof in the single oral dose is sufficient to achieve a bunidarone blood concentration of at least about 50 ng / mL in the patient for at least about 5 hours.

5. The method of claim 4, wherein the amount of bunidarone or a pharmaceutically acceptable salt thereof in the single oral dose is sufficient to achieve a blood concentration of bunidarone in the patient of at least about 50 ng / mL for at least about 6 hours.

6. The method of claim 2, wherein the bunidarone or a pharmaceutically acceptable salt thereof is administered orally using capsules, pills or tablets.

7. The method of claim 2, wherein the bunidarone or a pharmaceutically acceptable salt thereof is administered to the patient in a single oral dose of about 900 mg to about 1,200 mg.

8. The method of claim 2, wherein the bunidarone or a pharmaceutically acceptable salt thereof is administered in a single oral dose of about 1,000 mg.

9. The method of claim 2, wherein the bunidarone or a pharmaceutically acceptable salt thereof is administered in a single oral dose of about 1,200 mg.

10. The method of claim 2, further comprising administering an anticoagulant in combination with the bunidarone or a pharmaceutically acceptable salt thereof, wherein the anticoagulant comprises one or more of dabigatran, edoxaban, apixaban, or rivaroxaban.

11. The method of claim 2, wherein cardiac cardioversion is completed approximately 90 minutes or less after administration of the bunidarone or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein cardiac reversion is completed approximately 60 minutes or less after administration of the bunidarone or a pharmaceutically acceptable salt thereof.

13. The method of claim 11, wherein cardiac cardioversion is completed approximately 45 minutes or less after administration of the bunidarone or a pharmaceutically acceptable salt thereof.

14. The method of claim 11, wherein cardiac cardioversion is completed approximately 30 minutes or less after administration of the bunidarone or a pharmaceutically acceptable salt thereof.

15. The method of claim 2, wherein the patient eats about one hour or less before administering the bunidarone or a pharmaceutically acceptable salt thereof.

16. The method of claim 2, wherein the bunidarone or a pharmaceutically acceptable salt thereof comprises bunidarone tartrate.

17. A combination kit comprising: A single oral unit dose contains approximately 900 mg to approximately 2,000 mg of bunidarone or a pharmaceutically acceptable salt thereof. as well as Instructions for monitoring the patient's heart rate after administration should continue at least until the plasma concentration of bunidarone in the patient drops below 20 ng / mL.

18. A method for restoring a patient's heart to a normal sinus rhythm, the method comprising: Based on the determination that the patient requires cardiac cardioversion and is diagnosed with paroxysmal or persistent atrial fibrillation (AFib), the patient is given a single oral dose comprising at least about 900 mg of bunidarone or a salt thereof.

19. The method of claim 18, wherein the single oral dose comprises at least about 1,000 mg to about 2,000 mg.

20. The method of claim 18, wherein the single oral dose comprises at least about 900 mg to 1,200 mg in a single dose unit.

21. The method of claim 20, wherein the single dose unit is a pill, capsule, or tablet.

22. The method of claim 18, wherein the bunidarone salt is bunidarone tartrate.

23. The method of claim 18, further comprising monitoring the patient's heart rhythm after administration of the single oral dose.

24. The method of claim 23, wherein monitoring continues until the plasma concentration of bunidarone in the patient is measured to be below about 20 ng / mL, and until the patient's heart rhythm is restored to sinus rhythm.

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