Defibrillation using budiodarone

Abstract

A method for defibrillating a patient with paroxysmal or persistent atrial fibrillation using budiodarone or a pharmaceutical composition containing budiodarone is disclosed.

Description

[Technical Field]

[0001] cross reference This application claims the interests of U.S. Nonprovisional Application No. 18 / 351,261, filed on 12 July 2023, which in turn claims the interests of U.S. Provisional Application No. 63 / 525,014, filed on 5 July 2023, and these applications are each incorporated herein by reference in their entirety.

[0002] field This disclosure provides a cardioversion method for restoring sinus rhythm to patients with paroxysmal or persistent atrial fibrillation (AFib) using a pharmaceutical composition comprising budiodarone.

[0003] Related applications This application claims the benefits of U.S. Provisional Application No. 63 / 525,014, filed on 5 July 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0004] Patients with paroxysmal or persistent atrial fibrillation who experience prolonged episodes of atrial fibrillation are at high risk of stroke and / or congestive heart failure. These risks increase with the duration of the episode. Patients with symptomatic paroxysmal or persistent atrial fibrillation are significantly more likely to recognize their condition, whereas asymptomatic patients wearing heart rate monitors that alert for prolonged atrial fibrillation only become aware of their condition when the alarm sounds. In either case, many patients who present to the emergency room or intensive care unit with such prolonged episodes of atrial fibrillation are typically treated with defibrillation, a procedure that stops and restarts the heart to restore sinus rhythm. Currently, there are approximately 70,000 to possibly over 100,000 defibrillations performed annually, and this number is increasing with the aging population. These figures represent the proportion of patients who present to the emergency room with atrial fibrillation. One study suggests that approximately 25% of patients who present to the emergency room with atrial fibrillation are treated with defibrillation. Gulizia et al., Europace. 2019;21(2): 230-238. This suggests that among the patients who did not receive treatment, some had comorbidities for which the procedure was contraindicated, and others had restored sinus rhythm without defibrillation.

[0005] One option for defibrillation is electrical defibrillation, which relies on stopping and restarting the heart to restore sinus rhythm. However, this procedure has several drawbacks. From the patient's perspective, for example, there is a risk of death during or within a few months after the procedure because blood clots may be released from the heart during electrical defibrillation. From the clinician's perspective, electrical defibrillation requires at least one nurse, an anesthesiologist, a cardiologist, and the use of anticoagulants, all of which are costly for the healthcare system. From a cost perspective, defibrillation can cost thousands of dollars, and considering the number of defibrillations performed annually, especially if the treatment costs for patients who release blood clots during or immediately after the procedure are also included, it places a significant burden on the healthcare system. [Overview of the project] [Problems that the invention aims to solve]

[0006] A method for defibrillating a patient having a prolonged episode of paroxysmal or persistent atrial fibrillation is disclosed, the method comprising a single high-dose administration of budiodarone or a pharmaceutically acceptable salt thereof to defibrillate the atrial-sinus rhythm in the patient. The single high-dose budiodarone or a pharmaceutically acceptable salt thereof is preferably administered orally, but other routes of administration, including intravenous, rectal, and pulmonary administration, are also envisioned herein. The patient to be defibrillated is first determined to be suitable for the procedure. [Means for solving the problem]

[0007] In one embodiment, a method is provided for defibrillating a patient with paroxysmal or persistent atrial fibrillation suffering from a prolonged episode of atrial fibrillation, the method comprising: a) evaluating the patient to confirm that the patient has paroxysmal or persistent atrial fibrillation and is suitable for defibrillation; b) administering to the patient budiodarone or a pharmaceutically acceptable salt thereof in an amount sufficient to perform defibrillation to restore the patient's atrial fibrillation to sinus rhythm; and c) monitoring the patient after the administration to confirm that the patient responds to defibrillation.

[0008] In another embodiment, a method is provided for defibrillating a patient having paroxysmal or persistent atrial fibrillation with a prolonged episode of atrial fibrillation and who is deemed suitable for defibrillation, the method comprising: a) administering to the patient a sufficient amount of budiodarone or a pharmaceutically acceptable salt thereof to defibrillate the atrial fibrillation and restore sinus rhythm (where the patient has been confirmed to have paroxysmal or persistent atrial fibrillation and is deemed suitable for defibrillation); and b) monitoring the patient after the administration to confirm that the patient responds to defibrillation.

[0009] Further embodiments provide a method for defibrillating a patient with paroxysmal or persistent atrial fibrillation suffering from a prolonged episode of atrial fibrillation, the method comprising: a) administering to the patient an amount sufficient to achieve a plasma concentration of at least about 13 ng / ml for a certain period of time, thereby defibrillating the patient and restoring sinus rhythm (where the patient has been confirmed to have paroxysmal or persistent atrial fibrillation and is deemed suitable for defibrillation); and b) monitoring the patient after the administration to confirm that the patient responds to defibrillation.

[0010] In another embodiment, a method is provided for defibrillating a patient who has paroxysmal or persistent atrial fibrillation with a prolonged episode of atrial fibrillation and who is deemed suitable for defibrillation, the method comprising: a) Administer to the patient budiodarone or a pharmaceutically acceptable salt thereof in an amount sufficient to defibrillate the atrial fibrillation and restore sinus rhythm (where the patient has been confirmed to have paroxysmal or persistent atrial fibrillation); and b) Monitor the patient after administration to confirm that the patient responds to defibrillation.

[0011] Further embodiments provide a method for defibrillating a patient having paroxysmal or persistent atrial fibrillation who is suffering from a prolonged episode of atrial fibrillation, the method comprising: a) defibrillating the patient and restoring him to sinus rhythm by administering to him an amount sufficient to achieve a plasma concentration of at least about 13 ng / ml for a certain period of time (where the patient has been confirmed to have paroxysmal or persistent atrial fibrillation and is deemed suitable for defibrillation); and b) monitoring the patient after administration to confirm that the patient is responding to defibrillation.

[0012] In one embodiment, the amount of budiodarone 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 budiodarone or a pharmaceutically acceptable salt thereof. Monitoring of the patient's heart rate is preferably continued throughout the entire period while the plasma concentration of budiodarone or a pharmaceutically acceptable salt thereof is maintained at about 13 ng / mL. In a preferred embodiment, the plasma concentration of budiodarone or a pharmaceutically acceptable salt thereof ranges from about 13 ng / mL to about 350 ng / mL. max The range is up to. In another preferred embodiment, the plasma concentration of budiodarone or a pharmaceutically acceptable salt thereof is in the range of about 50 ng / mL to about 350 ng / mL, and any partial range of about 10 ng within the said range.

[0013] In one embodiment, budiodarone or a pharmaceutically acceptable salt thereof is administered orally, sublingually, intravenously (iv or IV), rectally, as an aerosol (in the lung), or as an intranasal spray, or in combination thereof. In one preferred embodiment, budiodarone or a pharmaceutically acceptable salt thereof is administered orally in the form of capsules, pills, or tablets. Considering the delivery efficiency and the amount required to provide the plasma concentrations shown above or herein, the dose of budiodarone or a pharmaceutically acceptable salt thereof when administered intravenously, sublingually, or as a spray may be lower than the dose required for oral administration.

[0014] As described above, the methods described herein involve administering to a patient an amount of budiodarone or a pharmaceutically acceptable salt thereof sufficient to restore atrial fibrillation to sinus rhythm by defibrillation, while the plasma concentration of budiodarone or a pharmaceutically acceptable salt thereof is maintained at or above the level defined herein. In most cases, in responsive patients, defibrillation is expected to occur within about 90 minutes, preferably within about 60 minutes, more preferably within about 45 minutes, or within about 30 minutes, after administration of budiodarone or a pharmaceutically acceptable salt thereof.

[0015] Generally, the amount of budiodarone or a pharmaceutically acceptable salt thereof used for defibrillation in a patient is a single bolus 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 budiodarone or a pharmaceutically acceptable salt thereof is administered as a single pill or capsule. In one preferred embodiment, the dose of budiodarone or a pharmaceutically acceptable salt thereof used, based on its half-life data, is coupled with maintaining a budiodarone therapeutic plasma concentration of at least about 13 ng / mL in the patient's body for about 6 hours, with a C concentration of at least about 50 ng / mL or higher. max The appropriate dose is selected by the clinician to achieve this. Preferred doses of budiodarone or its pharmaceutically acceptable salts to achieve such sustained retention of therapeutic concentrations include single doses of 800 mg, 1,000 mg, or 1,200 mg, or any dose between 800 mg and 1,200 mg. The dose of budiodarone or its pharmaceutically acceptable salt can also be increased by approximately 50 mg or 100 mg between 400 mg and 1,200 mg (e.g., 1,100 mg or 700 mg). Budiodarone in sublingual, intravenous, rectal, and spray forms is less than 1,200 mg and is expected to be in the range of approximately 10% to 50% of the 1,200 mg oral dose. Another embodiment envisions administering budiodarone or a pharmaceutically acceptable salt thereof to a patient by one or more means, for example, intravenously and orally, sublingually and orally, sublingually and by spray, or orally and intravenously, intravenously and by spray, or intravenously and sublingually. Intravenous administration is envisioned to induce a more rapid transition to sinus rhythm in patients who require it.

[0016] In one embodiment, administration of budiodarone or a pharmaceutically acceptable salt thereof is accompanied by administration of a second drug, such as an anticoagulant (e.g., dabigatran, edoxaban, apixaban, or rivaroxaban-Xarelto®).

[0017] Also provided is the use of budesonide or a pharmaceutically acceptable salt thereof for defibrillation of patients with paroxysmal or persistent atrial fibrillation who suffer from long-term atrial fibrillation episodes.

[0018] Another embodiment provides defibrillation of a single continuous long-term PAF episode, or a series of long-term PAF episodes, or a persistent atrial fibrillation episode in a patient, and restoration to normal sinus rhythm, by administering to a patient determined to require defibrillation and having paroxysmal or persistent atrial fibrillation, a dose of budesonide or a pharmaceutically acceptable salt thereof sufficient to obtain a plasma concentration in the patient of greater than 50 ng / ml within 60 minutes after administration, and maintaining the plasma concentration in the patient of greater than 50 ng / ml for up to 6 hours.

[0019] A further embodiment provides the use of budesonide or a pharmaceutically acceptable salt thereof for defibrillation of patients with paroxysmal or persistent atrial fibrillation who suffer from long-term atrial fibrillation episodes.

[0020] Yet another embodiment provides an oral dose of budesonide or a pharmaceutically acceptable salt thereof for use in defibrillating patients with paroxysmal or persistent atrial fibrillation who suffer from long-term atrial fibrillation episodes, comprising oral administration of from about 1,000 mg to about 2,000 mg of budesonide or a pharmaceutically acceptable salt thereof. The oral dose of budesonide or a pharmaceutically acceptable salt thereof can be delivered as a single bolus dose in increments of 50 mg between 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 between 1,000 mg and about 2,000 mg. The dosage form of from about 1,000 mg to about 2,000 mg of budesonide or a pharmaceutically acceptable salt thereof described in this paragraph can be a pill, tablet, or capsule.

[0021] In another embodiment, the pharmaceutically acceptable salt of budesonide is budesonide tartrate.

Brief Description of the Drawings

[0022] This patent or application documents contain at least one color drawing. Copies of this patent or patent application publication containing color drawings are provided by the Patent Office upon payment of the claims and required fees, in accordance with 37 C.F.R.§1.84.

[0023] [Figure 1] Figure 1 shows the change in plasma concentration over time using different single administrations of budiodarone. From the data, it can be seen that for each single administration of 400 mg or more, Cmax exceeded 50 ng / mL and a concentration exceeding approximately 13 ng / mL was maintained for more than 6 hours.

[0024] [Figure 2] Figure 2 shows a comparison of plasma budiodarone concentrations between fasting and fed patients.

Modes for Carrying Out the Invention

[0025] Detailed explanation The present disclosure relates to a method of cardioverting atrial fibrillation to sinus rhythm in patients having paroxysmal or persistent atrial fibrillation (Afib) and who have experienced atrial fibrillation for a long time. The methods described herein use budiodarone to cardiovert these patients. For terms not defined, their definitions are indicated in the context or a medically acceptable definition is provided.

[0026] The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. The singular forms "a", "an", and "the" used herein shall include the plural forms as well, unless the context clearly dictates otherwise.

[0027] Definitions As used herein, the terms “optional” or “optionally” mean that the events or situations described below may or may not occur, and that the descriptions include both cases in which the events or situations occur and cases in which they do not occur.

[0028] As used herein, the term "approximately" when used before numerical representations of temperature, time, quantity, concentration, and others (including ranges), indicates an approximate value that may vary by (+) or (-) 15%, 10%, 5%, 1%, or any sub-range between them. Preferably, when used in relation to dosage, the term "approximately" means that the dosage may vary by + / - 10%.

[0029] In this specification, the terms "comprising" or "comprise" mean that a composition or method includes the listed elements but does not exclude other elements.

[0030] In this specification, the term "consisting essentially of" used to define compositions and methods means excluding other elements that are essentially important to the expressed purpose of the combination. Accordingly, a composition consisting essentially of the elements defined herein or a method consisting essentially of the protocols defined herein does not exclude other components that do not substantially affect the basic and novel properties of the claimed subject matter.

[0031] As used herein, the term "consisting of" means excluding other components or substantial steps of the method beyond the trace element. Embodiments defined by each of these connecting terms are within the scope of this disclosure.

[0032] As used herein, the terms “atrial fibrillation (AFib)” or “atrial fibrillation” refer to all variants of atrial fibrillation except persistent atrial fibrillation. Such variants include, but are not limited to, paroxysmal atrial fibrillation, persistent atrial fibrillation, and paroxysmal and persistent atrial fibrillation with low CHA2DS2-VASc scores (≤2) and high CHA2DS2-VASc scores (≥3). The CHA2DS2-VASc score represents congestive heart failure (C-1 point), hypertension (H-1 point), age 75 years or older (A-2 points), diabetes (D-1 point), stroke (S-2 points), vascular disease (V-1 point), age 65–74 years (A-1 point), and sex (Sc-1 point for women), and is a clinical predictive rule for estimating stroke risk in patients with non-rheumatic atrial fibrillation (AF). The CHA2DS2-VASc score includes one or two points for each constituent risk factor, as described above.

[0033] As used herein, the term “prolonged atrial fibrillation” refers to the duration of an atrial fibrillation episode in a patient. The length of this duration is associated with the risk of stroke and / or heart failure. Clearly, the longer the duration of atrial fibrillation in a patient, the higher the risk. Thus, in one embodiment, prolonged atrial fibrillation refers to an atrial fibrillation episode that lasts for at least about 30 minutes, or at least about 1 hour, or at least 5 hours, provided that the patient has not been diagnosed with persistent atrial fibrillation.

[0034] As used herein, the term “paroxysmal atrial fibrillation” refers to sporadic and intermittent episodes of atrial fibrillation that last no more than seven days before returning to sinus rhythm. However, patients with mild atrial fibrillation may also have paroxysmal atrial fibrillation, although this is not always the case.

[0035] In this specification, the term “persistent atrial fibrillation” refers to sporadic and intermittent episodes of atrial fibrillation that persist for more than seven days and are unlikely to return to sinus rhythm without medical intervention (e.g., defibrillation).

[0036] As used herein, the term “budiodarone” refers to (S)-sec-butyl 2-(3-(4-(2-(diethylamino)ethoxy)-3,5-diiodobenzoyl)benzofuran-2-yl) acetate, and its pharmaceutically acceptable salts. In some cases, budiodarone tartrate is referred to as ATI-2042 or simply “2042”. Budiodarone, as a free base, is represented by the following formula: [ka] The pharmaceutically acceptable salts of this free base are included in the term “budiodarone” and encompass all approved pharmaceutically acceptable salts. Acceptable salts of budiodarone include budiodarone tartrate or budiodarone citrate. In one embodiment, the pharmaceutically acceptable salt may be a polycarboxylate salt. As is understood in the art, this salt dissociates from the free base in vivo. Furthermore, the main metabolite of budiodarone is a deacylated compound, i.e., a free acid. Therefore, when calculating the serum plasma concentration of budiodarone, the molar concentration and concentration are determined using the molecular weights of the free acid and free base. Furthermore, when administering salts other than tartrate, the dose of budiodarone tartrate used herein is necessarily modified to reflect the change in molecular weight due to the different salts.

[0037] Budiodarone has a complex mechanism of action and has been shown to reduce prolonged atrial fibrillation episodes without significantly prolonging the QT interval. Budiodarone has a cardiac ion channel effect similar to that of amiodarone, and delayed Na + The channel-blocking effect is enhanced. Budiodarone has a deliberately modified metabolism, resulting in a much shorter half-life than amiodarone, but it avoids the accumulation-related toxicity seen with amiodarone and is completely inactivated and eliminated from the body within hours to days after discontinuation.

[0038] In this specification, “single high dose” refers to a dose of budiodarone ranging from approximately 400 mg to approximately 1,200 mg, which is administered in one or more dose units to patients in need, or in a dosage form sufficient to achieve at least approximately 13 ng / mL of budiodarone. As stated above, a dosage form sufficient to achieve at least approximately 13 ng / mL of budiodarone to patients in need may be less than approximately 1,200 mg when administered by inhalation, sublingual, or intravenous administration, rather than by oral administration. These methods of administration can also be used in combination, and this is also considered when using the term “bolus.” When multiple dose units are used, they can be administered simultaneously with other dose units so that the total dose is administered within approximately 30 minutes, preferably within approximately 10 minutes. Furthermore, it should be noted that when taking a bolus of budiodarone, patients are asked to consume food, preferably a high-fat food, to achieve more rapid absorption of the drug into the body.

[0039] In this specification, "C max " " refers to the maximum plasma concentration of budiodarone after a single dose administered to a patient.

[0040] In this specification, "appropriate patient" or "patient" means a person who has experienced paroxysmal or persistent atrial fibrillation for approximately 6 hours or less, or a person who has experienced paroxysmal or persistent atrial fibrillation but has been determined to be free of thrombi by transesophageal echocardiography or other means of confirming the absence of thrombi in the patient, or a person who is known to have persistent or paroxysmal atrial fibrillation and is taking anticoagulants.

[0041] method The methods described herein involve defibrillating patients with prolonged atrial fibrillation using a single high-dose or bolus administration of budiodarone to restore sinus rhythm. These methods are used in patients diagnosed with paroxysmal or persistent atrial fibrillation. Patients with permanent atrial fibrillation do not respond to budiodarone, and treatment with this drug should be ruled out by the attending physician. For patients diagnosed with paroxysmal or persistent atrial fibrillation, who have prolonged atrial fibrillation and have presented to the emergency room or another facility capable of appropriately treating the patient, the clinician or caregiver should confirm that the arrhythmia is atrial fibrillation and not another known arrhythmia, and also determine that the patient is suitable for defibrillation.

[0042] After confirmation, the attending physician administers a single bolus (high dose) of budiodarone to the patient. The dose is sufficient to produce a budiodarone plasma concentration of at least about 13 ng / mL, which is maintained 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 one preferred embodiment, the amount of budiodarone administered to the patient ranges from about 800 mg, or at least about 1,000 mg, or at least about 1,200 mg of budiodarone in a single bolus. In some embodiments, a high-dose single dose of budiodarone is used to provide rapid uptake to therapeutic concentrations in vivo. When used in this manner, the plasma concentration of such a dose is less than about 350 ng / mL. max This reaches a level of at least approximately 40 ng / mL, or at least approximately 50 ng / mL, which is maintained for at least 5 hours, and in some cases, at least approximately 6 hours (see Figure 1). In any case, such high dose levels ensure that plasma concentrations are maintained at or above approximately 13 ng / mL, and in practice, at or above approximately 40 ng / mL for up to approximately 6 hours.

[0043] Following a bolus administration of budiodarone, the patient is placed under observation in the emergency room, ward, or other emergency medical facility, and their heart rate is monitored for a sufficient time to determine if they are responding to budiodarone. Once the heart has returned to sinus rhythm and the plasma concentration of budiodarone has decreased to a level satisfactory to the attending physician, the patient can be discharged unless there are other comorbidities requiring further observation. In one preferred embodiment, such a level is less than approximately 20 ng / mL, preferably less than approximately 15 ng / mL. In one preferred embodiment, the patient needs to be placed under observation for a short period (e.g., about 30 minutes to about 6 hours) to ensure that sinus rhythm is maintained.

[0044] Patients who respond to the above method can be discharged wearing a device that records their heart rate and selectively transmits it to check the degree and duration of atrial fibrillation. Patients who do not respond to the above method can be treated with electrical defibrillation.

[0045] Pharmaceutical composition A specific dose of budiodarone can be achieved by any number of acceptable methods of administration, including oral, intravenous, rectal, and pulmonary administration. Pharmaceutical compositions suitable for each of these administrations are well known in the art, as are methods useful for such administration. Preferably, oral administration is preferred, typically using tablets, pills, capsules, etc. The specific form used for oral administration is not particularly important.

[0046] The pharmaceutical dosage forms of budiodarone can be manufactured by any method well known in the art, such as conventional mixing, tableting, or encapsulation. 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.

[0047] The composition may include a drug in combination with at least one pharmaceutically acceptable excipient. The acceptable excipient is non-toxic, aids administration, and does not adversely affect the therapeutic effect of the claimed compound. Such excipient may be any solid, liquid, or semi-solid that is generally available to those skilled in the art.

[0048] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, and dried skim milk. Other suitable pharmaceutical excipients and their formulations are described in REMINGTON'S PHARMACEUTICAL SCIENCES, edited by EW Martin (Mack Publishing Company, 18th ed., 1990).

[0049] The compositions disclosed herein may, if necessary, be provided in disposable packaging. Such packaging may include metal foil or plastic foil, for example, blister packs, vials, or any other type of container. The packs or dispenser devices may be accompanied by instructions for administration, such as instructions for use.

[0050] The amount of drug in a formulation may be varied depending on the number of subunits required for the daily or regular dose of the drug. Typically, a formulation contains about 10–99% by weight of the drug based on the entire formulation, with the remainder being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 20–70% by weight. [Examples]

[0051] This disclosure will be further understood by reference to the following embodiments, which are purely illustrative of the invention. The scope of this disclosure is not limited by the illustrated embodiments, which are intended to illustrate only one aspect of this disclosure. All functionally equivalent methods are within the scope of this disclosure. Various modifications of the invention other than those described herein will be apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are included in the accompanying claims. In these embodiments, the following terms are used herein and have the following meanings. Unless defined, abbreviations have their conventional medical meanings.

[0052] Please note that the budiodarone concentrations used in the following examples include both the free acid and free base forms of budiodarone.

[0053] The following abbreviations used in this specification have the meanings set forth below. Unless otherwise defined, abbreviations have their general meanings. [Table 1]

[0054] Example 1 - Measurement of the minimum concentration of budiodarone to shorten the duration of atrial fibrillation In this study, patients were selected for prolonged episodes of paroxysmal or persistent atrial fibrillation. Each patient had a pacemaker implanted to monitor their heart rate. Next, baseline values ​​for the duration of atrial fibrillation episodes were obtained by assessing disease progression in patients by monitoring their heart rate without budiodarone treatment. Baseline data were collected over two weeks. Patients were then given budiodarone in escalating doses of 200 mg twice daily, 400 mg twice daily, 600 mg twice daily, and 800 mg twice daily, maintaining each dose for two weeks, for a total of four treatment periods. A two-week washout period was observed after the completion of the 800 mg twice daily treatment period. The washout period is a period after the last treatment to avoid misinterpretation of study-related treatment observations that may be attributable to previous treatments. Pacemaker data were downloaded on days 8 and 14 of each two-week cycle, and the mean values ​​for each study period are shown. Blood samples were taken during each cycle to measure budiodarone levels. The results of this study are as follows: [Table 2] Note that at all dosage levels from 400 mg twice daily to 800 mg twice daily, the duration of atrial fibrillation was less than 90 minutes for the maximum duration of atrial fibrillation, and in practice, less than 60 minutes and less than 45 minutes. When 600 mg was administered twice daily, the longest average duration of atrial fibrillation was 6 minutes (less than 30 minutes). Also note that the trough Pk value of budiodarone is based on administration at approximately 12-hour intervals and is unrelated to the trough value 6 hours after administration.

[0055] This data shows that a bolus dose of budiodarone results in a plasma concentration of at least 50 ng / mL. maxThis supports the basis for rapidly reaching that concentration and maintaining it for a sufficient time to restore the patient's atrial fibrillation to sinus rhythm by defibrillation. Also, the elimination of bupropion from the blood is rapid, and the plasma trough concentration 2 weeks after administering 800 mg of bupropion twice daily corresponds to 0.3 ng / mL, which is approximately 1.5% of the trough concentration of 19.8 ng / mL when 800 mg of bupropion is administered twice daily. It should be noted that this indicates that the drug disappears rapidly after discontinuation of administration.

[0056] Example 2: Measurement of bupropion plasma concentration over time using different doses In this example, different single doses of bupropion were used to evaluate the plasma concentration of bupropion. Specifically, as shown in FIG. 1, bupropion was administered to patients at single doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1000 mg. Blood samples were taken from each patient, and the concentration of bupropion or its inactive deacylated metabolite was measured. The obtained data were shown on a graph, and for each concentration data, both the C max and the trough value 6 hours later were shown.

[0057] Specifically, FIG. 1 demonstrates that the plasma concentration of a single dose of bupropion of 400 mg or more results in a C max exceeding 50 ng / mL within 60 minutes after single oral administration and maintains a plasma concentration exceeding approximately 13 ng / mL for over 6 hours each. Furthermore, a single dose of 800 mg or 1,000 mg of bupropion will result in a plasma concentration of approximately 50 ng / mL at 6 hours and at least approximately 15 ng / mL at 8 hours.

[0058] This data also shows that, for example, by a bolus administration of 1,000 mg of bupropion, the C maxThe drug is rapidly absorbed to concentrations exceeding 300 ng / mL, and this is rapidly excreted to less than 20 ng / mL in approximately 8 hours. In summary, rapid uptake combined with rapid excretion makes bolus administration suitable for defibrillation, as high doses of budiodarone rapidly reach effective concentrations in the body within 60 minutes of administration, maintain plasma concentrations above approximately 13 ng / mL for at least 6 hours, and then rapidly excrete from the body. In summary, these data suggest that budiodarone rapidly transitions prolonged atrial fibrillation episodes into significantly shorter episodes or eliminates atrial fibrillation, thereby defibrillating the patient and restoring sinus rhythm within 90 minutes of drug administration.

[0059] Because budiodarone has been proven safe for oral administration in clinical trials, defibrillation using budiodarone serves as an alternative to electrical defibrillation and its associated problems.

[0060] Example 3 - Effect of diet on budiodarone concentration This study evaluates the effect of fasting and feeding on plasma budiodarone concentrations. In this study, patients were either fasted or fed before budiodarone administration. After budiodarone administration, blood samples were collected from the patients and budiodarone plasma concentrations were measured. Figure 2 shows the effect of the same budiodarone dose on C max As is clear from the values, this indicates an increase in budiodarone uptake. However, C in the feeding group max C is a fasting patient maxNote that this is approximately one hour later than previously thought. This suggests that fasting patients undergoing budiodarone defibrillation should preferably eat within approximately one hour (about 60 minutes) of the start of defibrillation. This data indicates that, regardless of whether the drug is taken with food, a single oral dose of 400-1,000 mg achieves an effective plasma concentration of over 50 ng / mL within 60 minutes, and maintaining this concentration and higher concentrations for up to 6 hours is sufficient to defibrillate a single prolonged, sustained PAF (paroxysmal atrial fibrillation) episode, or a sustained or series of prolonged atrial fibrillation episodes that cause symptoms requiring emergency room transport, and restore normal sinus rhythm.

[0061] Embodiment The following embodiments are envisioned.

[0062] [1] A method for defibrillating a patient having paroxysmal or persistent atrial fibrillation with a prolonged episode of atrial fibrillation and who is deemed suitable for defibrillation, comprising: a) administering to the patient a sufficient amount of budiodarone or a pharmaceutically acceptable salt thereof to defibrillate the atrial fibrillation and restore sinus rhythm (where the patient has been confirmed to have paroxysmal or persistent atrial fibrillation); and b) monitoring the patient after administration to confirm that the patient responds to defibrillation.

[0063] [2] A method for defibrillating a patient with paroxysmal or persistent atrial fibrillation suffering from a prolonged episode of atrial fibrillation, comprising: a) administering to the patient an amount sufficient to achieve a plasma concentration of at least about 13 ng / ml of budiodarone or a pharmaceutically acceptable salt thereof for a certain period of time, thereby defibrillating the patient and restoring him to sinus rhythm (where the patient has been confirmed to have paroxysmal or persistent atrial fibrillation and is deemed suitable for defibrillation); and b) monitoring the patient after the administration to confirm that the patient responds to defibrillation.

[0064] [3] The amount of budiodarone or a salt thereof administered to the patient is sufficient to provide a plasma concentration of about 13 ng / mL to about 350 ng / mL in the patient, provided that the plasma concentration of budiodarone is greater than at least about 13 ng / mL for at least 6 hours after administration, according to one embodiment [1] or [2].

[0065] [4] The method according to one embodiment [1] or [3], wherein the amount of budiodarone or a salt thereof administered to the patient is sufficient to provide the patient with a plasma concentration of budiodarone or a salt thereof of about 50 ng / mL to about 350 ng / mL for at least about 5 hours.

[0066] [5] The method according to Embodiment [4], wherein the amount of budiodarone or a salt thereof administered to the patient is sufficient to provide the patient with a plasma concentration of budiodarone or a salt thereof of about 50 ng / mL to about 350 ng / mL for at least about 6 hours.

[0067] [6] The method according to any one of embodiments [1] to [5], wherein the administration of budiodarone or a salt thereof is by oral administration, sublingual administration, intravenous administration, rectal administration, or aerosol administration.

[0068] [7] The method according to any one of embodiments [1] to [6], wherein budiodarone or a salt thereof is administered orally in the form of capsules, pills, or tablets.

[0069] [8] The method according to any one of embodiments [1] to [7], wherein the dose of budiodarone or a salt thereof is administered as a single dose of about 400 mg to about 2,000 mg.

[0070] [9] The method of the embodiment [8], wherein the aforementioned dose of budiodarone or a salt thereof is administered as a single dose of about 800 mg to about 1,200 mg.

[0071]

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

[0072]

[11] The method according to embodiment [8], wherein the aforementioned dose of budiodarone or a salt thereof is administered as a single dose of about 1,200 mg.

[0073]

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

[11] , further comprising administering the anticoagulant, which is dabigatran, edoxaban, apixaban, or rivaroxaban, together with budiodarone or a salt thereof.

[0074]

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

[12] , wherein defibrillation of the patient is performed within approximately 90 minutes of administration of budiodarone or a salt thereof.

[0075]

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

[12] , wherein defibrillation is performed within approximately 60 minutes of administration of budiodarone or a salt thereof.

[0076]

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

[12] , wherein defibrillation is performed within approximately 45 minutes of administration of budiodarone or a salt thereof.

[0077]

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

[12] , wherein defibrillation is performed within approximately 30 minutes of administration of budiodarone or a salt thereof.

[0078]

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

[12] , wherein the patient ingests budiodarone or a salt thereof within about one hour before administration.

[0079]

[18] A kit comprising a single dose of budiodarone or a pharmaceutically effective salt thereof effective for defibrillating a patient, and instructions for monitoring the patient after administration.

[0080]

[19] Administration of a certain dose of budiodarone or a pharmaceutically acceptable salt thereof for defibrillation of a patient determined to have paroxysmal or persistent atrial fibrillation, wherein the dose results in an effective plasma level of greater than 50 ng / ml in the patient within about 60 minutes after administration and maintains a plasma concentration greater than 50 ng / ml in the patient for up to 6 hours, thereby defibrillating a single prolonged episode of persistent PAF or a series of prolonged PAF episodes or episodes of persistent atrial fibrillation in the patient that caused the symptoms, thereby restoring normal sinus rhythm.

[0081]

[20] Use of budiodarone or a pharmaceutically acceptable salt thereof to defibrillate a patient having paroxysmal or persistent atrial fibrillation suffering from a prolonged episode of atrial fibrillation by administering a dose of budiodarone according to any one of the methods described in Embodiments [1] to

[19] .

[0082]

[21] An oral dose of budiodarone or a pharmaceutically acceptable salt thereof as described in Embodiment

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

[0083]

[22] Oral doses of budiodarone or a pharmaceutically acceptable salt thereof as described in Embodiment

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

[0084]

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

[21] to

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

[0085]

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

[20] to

[23] , wherein the budiodarone salt is budiodarone tartrate.

Claims

1. A method for defibrillating a patient with paroxysmal or persistent atrial fibrillation suffering from a prolonged episode of atrial fibrillation, who is deemed suitable for defibrillation, comprising the following: a) Administer to the patient budiodarone or a pharmaceutically acceptable salt thereof in an amount sufficient to defibrillate the atrial fibrillation and restore sinus rhythm (where the patient has been confirmed to have paroxysmal or persistent atrial fibrillation); and b) Monitor the patient after administration to confirm that the patient responds to defibrillation.

2. A method for defibrillating a patient with paroxysmal or persistent atrial fibrillation suffering from a prolonged episode of atrial fibrillation, comprising the following: a) Defibrillating the patient and restoring sinus rhythm by administering to the patient an amount of budiodarone or a pharmaceutically acceptable salt thereof sufficient to achieve a plasma concentration of at least about 13 ng / ml of budiodarone or a pharmaceutically acceptable salt thereof for a certain period of time (where the patient has been confirmed to have paroxysmal or persistent atrial fibrillation and is deemed suitable for defibrillation); and b) After administration, monitor the patient to confirm that the patient responds to defibrillation.

3. The method according to claim 1, wherein if the plasma concentration of budiodarone is greater than at least about 13 ng / mL for at least 6 hours after administration, the amount of budiodarone or a salt thereof administered to the patient is sufficient to provide a plasma concentration of about 13 ng / mL to about 350 ng / mL in the patient.

4. The method according to claim 3, wherein the amount of budiodarone or a salt thereof administered to the patient is sufficient to provide the patient with a plasma concentration of budiodarone or a salt thereof of about 50 ng / mL to about 350 ng / mL for at least about 5 hours.

5. The method according to claim 4, wherein the amount of budiodarone or a salt thereof administered to the patient is sufficient to provide the patient with a plasma concentration of budiodarone or a salt thereof of about 50 ng / mL to about 350 ng / mL for at least about 6 hours.

6. The method according to claim 1, wherein the administration of budiodarone or a salt thereof is by oral administration, sublingual administration, intravenous administration, rectal administration, or aerosol administration.

7. The method according to claim 6, wherein budiodarone or a salt thereof is administered orally in the form of capsules, pills, or tablets.

8. The method according to claim 7, wherein budiodarone or a salt thereof is administered to the patient in a single dose of about 400 mg to about 2,000 mg.

9. The method according to claim 8, wherein budiodarone or a salt thereof is administered to the patient in a single dose of about 800 mg to about 1,200 mg.

10. The method according to claim 8, wherein budiodarone or a salt thereof is administered as a single dose of about 1,000 mg.

11. The method according to claim 8, wherein budiodarone or a salt thereof is administered as a single dose of about 1,200 mg.

12. The method according to claim 1, further comprising administering the anticoagulant, which is dabigatran, edoxaban, apixaban, or rivaroxaban, together with budiodarone or a salt thereof.

13. The method according to claim 1, wherein defibrillation is performed within approximately 90 minutes of administration of budiodarone or a salt thereof.

14. The method according to claim 13, wherein defibrillation is performed within approximately 60 minutes of administration of budiodarone or a salt thereof.

15. The method according to claim 13, wherein defibrillation is performed within approximately 45 minutes of administration of budiodarone or a salt thereof.

16. The method according to claim 13, wherein defibrillation is performed within approximately 30 minutes of administration of budiodarone or a salt thereof.

17. The method according to claim 1, wherein the patient ingests budiodarone or a salt thereof within approximately one hour before administration.

18. The method according to claim 1, wherein the budiodarone or a salt thereof is budiodarone tartrate.

19. A kit comprising a component containing a single dose of budiodarone or a salt thereof effective for defibrillating a patient, and instructions for post-administration monitoring of the patient.

20. A method comprising defibrillating a patient to restore normal sinus rhythm, A method comprising administering a certain dose of budiodarone or a salt thereof to a patient who is determined to have paroxysmal or persistent atrial fibrillation and requires defibrillation (wherein the dose is sufficient to produce an effective plasma concentration greater than 50 ng / ml in the patient within 60 minutes after administration of the dose), and maintaining the patient's plasma concentration greater than 50 ng / ml for up to 6 hours, thereby defibrillating a single prolonged episode of persistent PAF, or a series of prolonged PAF episodes, or a prolonged episode of persistent atrial fibrillation in the patient to restore normal sinus rhythm.

21. The method according to claim 20, wherein the dose comprises at least about 1,000 mg to about 2,000 mg.

22. The method according to claim 20, wherein the dose comprises at least about 900 mg to 1200 mg.

23. The method according to claim 22, wherein the administration unit is a pill, a capsule, or a tablet.

24. The method according to claim 20, wherein the budiodarone salt is budiodarone tartrate.

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