WO2010114562A1 - Improved methods of administration of k201 (jtv-519) (4-[3-{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy 2, 3, 4, 5-tetrahydro-1, 4-benzothiazepine monohydrochloride) - Google Patents

Improved methods of administration of k201 (jtv-519) (4-[3-{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy 2, 3, 4, 5-tetrahydro-1, 4-benzothiazepine monohydrochloride) Download PDF

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WO2010114562A1
WO2010114562A1 PCT/US2009/039536 US2009039536W WO2010114562A1 WO 2010114562 A1 WO2010114562 A1 WO 2010114562A1 US 2009039536 W US2009039536 W US 2009039536W WO 2010114562 A1 WO2010114562 A1 WO 2010114562A1
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subject
heart failure
administration
cardiac
hours
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PCT/US2009/039536
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French (fr)
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Paul Chamberlin
Howard Dittrich
Brian Farmer
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Sequel Pharmaceuticals, Inc.
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Priority to PCT/US2009/039536 priority Critical patent/WO2010114562A1/en
Publication of WO2010114562A1 publication Critical patent/WO2010114562A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem

Definitions

  • the embodiments disclosed herein relate to methods of treating and/or preventing cardiac disorders using a benzothiazepine derivative. Description of the Related Art
  • Atrial flutter and/or atrial fibrillation are the most commonly sustained cardiac arrhythmias in clinical practice, and are likely to increase in prevalence with the aging of the population.
  • AF Atrial flutter and/or atrial fibrillation
  • AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases and causes more than 80,000 strokes each year in the United States.
  • AF is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism.
  • Class I and Class III antiarrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects, including ventricular proarrhythmia.
  • antiarrhythmic agents of Class I according to the classification scheme of Vaughan- Williams (''Classification of antiarrhythmic drugs," Cardiac Arrhythmias, edited by: E. Sandoe, E. Flensted-Jensen, K. Olesen; Sweden, Astra, Sodertalje, pp 449-472 (1981)), which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (V max ) are inadequate for preventing cardiac disorders such as ventricular fibrillation because they shorten the wavelength of the cardiac action potential, thereby favoring re-entry.
  • Class II and Class IV antiarrhythmics while having a higher safety margin than the Class I agents, are also of limited therapeutic value.
  • ⁇ -adrenergenic receptor blockers and calcium channel (lea) antagonists which belong to Class II and Class IV, respectively, are of limited therapeutic values as their therapeutic effects is are limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease.
  • Class III antiarrhythmic agents function by increasing myocardial refractoriness via a selective prolongation of cardiac action potential duration (APD).
  • prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e., Na + or Ca 2+ currents; hereinafter I ⁇ and Ic a , respectively) or by reducing outward repolarizing potassium K + currents.
  • the delayed rectifier (I K ) K + current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (I t0 ) and inward rectifier (I K i) K + currents are responsible for the rapid initial and terminal phases of repolarization, respectively.
  • I K consists of two pharmacologically and kinetically distinct K + current subtypes, I ⁇ r (rapidly activating and deactivating and I ⁇ s (slowly activating and deactivating).
  • I ⁇ r rapidly activating and deactivating
  • I ⁇ s slowly activating and deactivating
  • I ⁇ r is the product of the human ether-a-go-go gene (hERG).
  • hERG cDNA in cell lines leads to production of a hERG current which is almost identical to I ⁇ r (Curran et al., "A molecular basis for cardiac arrhythmia: hERG mutations cause long QT syndrome," Cell 80(5):795-803 (1995)).
  • Class III antiarrhythmic agents including d-sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and methanesulfonamide- N-[ 1 '-6-cyano- 1 ,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro-4-hydroxyspiro[2H- 1 - benzopyran-2,4'-piperidin]-6-yl], (+)-, monochloride A-499) predominantly, if not exclusively, block I ⁇ r- Amiodarone also blocks I Na and Ic a , effects thyroid function, is as a nonspecific adrenergic blocker, acts as an inhibitor of the enzyme phospholipase, and causes pulmonary fibrosis (Nademanee, K
  • I ⁇ r blockers increase APD and refractoriness both in atria and ventricle without affecting conduction per se, theoretically they represent potential useful agents for the treatment of arrhythmias-like AF and VF. These agents have a liability, however, in that they have an enhanced risk of proarrhythmia at slow heart rates.
  • Torsade de Pointes a specific type of polymorphic ventricular tachycardia which is commonly associated with excessive prolongation of the electrocardigraphic QT interval, hence termed “acquired long QT syndrome", has been observed when these compounds are utilized (Roden, D. M. "Current Status of Class III Antiarrhythmic Drug Therapy", Am J. Cardiol, 72:44B-49B (1993)).
  • the exaggerated effect at slow heart rates has been termed "reverse frequency-dependence" and is in contrast to frequency-independent or frequency- dependent actions.
  • the slowly activating component of the delayed rectifier potentially overcomes some of the limitations of I ⁇ r blockers associated with ventricular arrhythmias. Because of its slow activation kinetics, however, the role of I ⁇ s in atrial repolarization may be limited due to the relatively short APD of the atrium. Consequently, although I KS blockers may provide distinct advantage in the case of ventricular arrhythmias, their ability to affect supra-ventricular tachyarrhythmias (SVT) is considered to be minimal.
  • SVT supra-ventricular tachyarrhythmias
  • Class III antiarrhythmic agents Another major defect or limitation of most currently available Class III antiarrhythmic agents is that their effect increases or becomes more manifest at or during bradycardia or slow heart rates, and this contributes to their potential for proarrhythmia. On the other hand, during tachycardia or the conditions for which these agents or drugs are intended and most needed, they lose most of their effect.
  • Embodiments disclosed herein relate to methods of preventing and/or treating a cardiac disorder in a subject with K201 or a pharmaceutically acceptable salt, ester, or amide thereof.
  • the K201 dosing regimen is calculated based upon the pharmacokinetics of a metabolite of K201 , e.g., the M-II metabolite, as the M-II metabolite has antiarrhythmic properties, as disclosed herein.
  • the administration of K201 can be according to a dosing schedule, wherein the dosing schedule requires no more than three temporally-spaced doses per day.
  • the dosing schedule requires no more than two doses per day.
  • the K201 can be administered in an oral dosage form.
  • the subject can have congestive heart failure, e.g., either systolic and/or diastolic heart failure.
  • the subject is administered multiple, temporally spaced doses of the K201 formulation over multiple days, according to a dosing schedule.
  • the spacing between at least some doses is an interval T3, wherein T3 is greater than T2.
  • T3 can be selected such that the subject has a blood level of the K201 metabolite Mil at T3 such that either the level of Mil or the combined levels of Mil and K201 at T3 are effective to treat or prevent arrhythmia in the subject.
  • the subject can have heart failure, e.g., systolic and/or diastolic heart failure.
  • Also provided herein is a method of treating or preventing a cardiac arrhythmia in a subject in need thereof, by providing a therapeutically effective amount of K201 or a pharmaceutically acceptable salt, ester, or amide thereof to a subject identified as suffering from or being at risk of cardiac arrhythmia, and informing the subject or medical care worker that administration can provide antiarrhythmic effects for a period of time following administration of the composition, wherein the time period exceeds the half life of K201. In some embodiments, the time period is at least six hours.
  • the subject or medical care worker can be informed that the antiarrhythmic effects can last for a time period, wherein the time period exceeds the half life of K201, or for a time period that is longer than the time period between the peak and trough of the plasma levels of K201, or for a time period that exceeds the time period for which a therapeutically adequate plasma level of K201 exists in a subject following administration of K201.
  • the time period can be at least six hours, e.g., seven hours, eight hours, nine hours, ten hours, eleven hours, twelve hours, or more.
  • the time period is twelve hours or greater.
  • K201 can be administered to the patient.
  • the subject can have heart failure, e.g., systolic and/or diastolic heart failure.
  • Also provided herein are methods for treating a subject that involve designing a course of therapy that is intended to achieve antiarrhythmic effects for at least a predetermined period, wherein the course of therapy includes the administration of more than one dose of a therapeutically effective amount of K201 or a pharmaceutically acceptable salt, ester, or amide thereof, and wherein when the time period between the sequential doses of K201 exceeds the half-life of K201; and administering K201 to the subject according to the designed course of therapy, wherein the subject has or is at risk of developing a cardiac arrhythmia.
  • the subject has congestive heart failure, e.g., systolic heart failure and or diastolic heart failure.
  • the time period exceeds the half life of K201, or for a time period that is longer than the time period between the peak and trough of the plasma levels of K201, or for a time period that exceeds the time period for which a therapeutically adequate plasma level of K201 exists in a subject following administration of K201.
  • the time period can be at least six hours, e.g., seven hours, eight hours, nine hours, ten hours, eleven hours, twelve hours, or more.
  • Some embodiments provide methods of treating or preventing a cardiac disorder in a subject in need thereof by providing a therapeutically effective amount of K201 or a pharmaceutically acceptable salt, ester, or amide thereof to a subject having or at risk of a cardiac disorder, informing the subject or medical care worker that administration can provide antiarrhythmic effects for a period of time following administration of the composition, wherein the time period exceeds the half life of K201; and administering the K201 to the subject.
  • the subject has congestive heart failure, e.g., systolic heart failure and or diastolic heart failure.
  • the time period exceeds the half life of K.201, or for a time period that is longer than the time period between the peak and trough of the plasma levels of K201, or for a time period that exceeds the time period for which a therapeutically adequate plasma level of K201 exists in a subject following administration of K201.
  • the time period can be at least six hours, e.g., seven hours, eight hours, nine hours, ten hours, eleven hours, twelve hours, or more.
  • the cardiac disorder can be an atrial cardiac rhythm disorder selected from the group consisting of atrial fibrillation, atrial flutter, or other supraventricular tachycardia.
  • the cardiac disorder can be ventricular tachycardia, ventricular fibrillation, Torsades des Pointes, catecholaminergic polymorphic ventricular tachycardia, monomorphic ventricular tachycardia, sudden cardiac death, acute and/or chronic cardiomyopathy, acute coronary syndrome, e.g., myocardial infarction or angina, acute and/or chronic hypertension.
  • acute and/or chronic hypertension is catecholamine-induced hypertension, pulmonary edema, chronic obstructive pulmonary disease, or the like.
  • Figure 1 is a graph of the concentration-response of the K201 metabolite M-II on the hERG potassium channel, as tested as described in Example 4.
  • Figure 2 is a graph of the concentration-response of the K201 metabolite M-II on the hNavl .5 sodium channel, as tested as described in Example 4.
  • Figure3 is a graph of the concentration-response of the K201 metabolite M-II on the hKvl .5 potassium channel, as tested as described in Example 4.
  • Figure 4 is a graph of the concentration-response of the K201 metabolite M-II on the L-type calcium channels (hCavl.2), as tested as described in Example 4.
  • Figure 5 is a graph of the concentration-response of the K201 metabolite M-II on the T-type calcium channels (hCav3.2), as tested as described in Example 4.
  • Figure 6 is a graph of the concentration-response of the K201 metabolite M-II on the hKir3.1/3.4 potassium channel, as tested as described in Example 4.
  • Figure 7 is a graph of the concentration-response of the K201 metabolite M-II on the hKir6.2/SUR2A potassium channels, as tested as described in Example 4.
  • Figures 8A-8B are graphs showing the effect of the K201 metabolite M-II on the right atrial effective refractory period following administration, expressed in the ms ( Figure 8A), or as a % increase from baseline (BL) ( Figure 8B).
  • Figures 8C-8D are graphs showing the effect of the K201 metabolite M-II on the left atrial effective refractory period following administration, expressed in the ms ( Figure 8C), or as a % increase from baseline (BL) ( Figure 8D).
  • Figure 9 is a graph showing the effect of the K201 metabolite M-II on the left ventricular effective refractory period following administration, expressed in the ms.
  • Figures 10A-10B are graphs showing the effect of administration of the K201 metabolite M-II on inter-atrial conduction time, from the left atrium to right atrium ( Figure 10A) and from the right atrium to the left atrium ( Figure 10B).
  • Figures 11A-11B are graphs showing the effect of administration of the K.201 metabolite M-II on systolic, diastolic, and mean blood pressure, either before the measurement ( Figure HA), or after the measurements of atrial and ventricular effective refractory periods and conduction times (Figure HB).
  • Figures 12A-12B are graphs showing the length of sinus cycle (in ms) over time, following infusion of the K201 metabolite M-II, either before the measurement ( Figure 12A), or after the measurements of atrial and ventricular effective refractory periods and conduction times (Figure 12B).
  • K201 is a compound that has both in vitro and in vivo antiarrhythmic properties and can be used for treatment of arrhythmias in both the short term (termination of arrhythmia) and chronic settings (prevention of arrhythmia, or maintenance of sinus rhythm).
  • K201 is rapidly metabolized such that even relatively high doses, given relatively frequently, would not result in therapeutically adequate plasma levels of K201.
  • K201 is metabolized via cytochrome P450 isoforms CYP 3A4 and 2D6.
  • the structure of K201 and its metabolites are shown in Table 1, below:
  • the embodiments disclosed herein are based, in part, on the surprising discovery that metabolites of K201, including M-II, have a blocking effect on cardiac ion channels as shown in the Examples below. As such, the data demonstrate that M-II, as well as K201 , is useful in the treatment and prevention of cardiac diseases and disorders, including cardiac arrhythmias. Accordingly, described herein are methods of administration of K201 to achieve desired antiarrhythmic effects at a frequency and dose based upon the elimination pharmacokinetic properties of the M-II metabolite.
  • Described herein are methods that involve administration of K201 less frequently than necessary to maintain a therapeutically effective concentration of K201 in plasma, while maintaining a therapeutically effective plasma concentration of M-II to maintain a continuous antiarrhythmic effect in a subject in need thereof.
  • An ideal dosage regimen for therapeutics is that by which an acceptable therapeutic concentration of drug at the site(s) of action is attained quickly and then is maintained constant, and above a minimal effective concentration (MEC) for the duration of the treatment.
  • MEC minimal effective concentration
  • the dose size and frequency of administration are designed to give a prompt "steady-state" plasma concentration of a drug.
  • the embodiments provided herein relate to methods of treating or preventing a cardiac disease or disorder in a subject.
  • cardiac disorder includes, but is not limited to, disorders such as cardiac rhythm disorders, such as atrial cardiac rhythm disorders or ventricular cardiac rhythm disorders.
  • Exemplary atrial cardiac rhythm disorders include atrial fibrillation, atrial flutter, other supraventricular tachycardias, and the like.
  • Exemplary ventricular cardiac disorders include, but are not limited to ventricular tachycardia, e.g., Torsade des Pointes, catecholaminergic polymorphic ventricular tachycardia, and monomorphic ventricular tachycardia.
  • cardiac disorder also encompasses conditions such as sudden cardiac death, acute and/or chronic heart failure, e.g., left ventricular systolic dysfunction or left ventricular diastolic dysfunction.
  • Other exemplary cardiac disorders include, but are not limited to acute coronary syndrome, such as myocardial infarction, angina, or the like, or acute and/or chronic hypertension, e.g., catecholamine-induced hypertension.
  • Still other exemplary cardiac disorders include but are not limited to pulmonary edema, chronic obstructive pulmonary disease and the like.
  • Preferred embodiments relate to the prevention or treatment of atrial fibrillation, e.g., in a subject that has heart failure, or, in other embodiments, in a subject that does not have heart failure.
  • subject refers to a vertebrate, preferably a mammal, more preferably a human.
  • mammal can refer to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as, for example, horses, sheep, cows, pigs, dogs, cats, etc.
  • the mammal is human.
  • the subject can be identified a "candidate" for a cardiac disorder.
  • a “candidate” for a cardiac disorder is a subject who is known to be, or who is believed to be, or is suspected of being at risk for developing a cardiac disorder, or who is known to have, believed to have, or is suspected of having an existing cardiac disorder.
  • any routine diagnostic technique, or any combination of techniques can be used to identify a subject that is a candidate for a cardiac disorder.
  • the rate and regularity of a subject's heart are assessed by checking the subject's pulse, measuring the subject's systolic blood pressure and/or the subject's diastolic blood pressure.
  • blood tests e.g., measuring a subject's serum cholesterol, high density lipoproteins, low density lipoproteins and triglycerides, as well as other markers indicative of heart disease, are used to identify candidate subjects.
  • the C - reactive protein (CRP) testing for instance can be used to determine whether a subject is at risk of developing a cardiac disorder, such as heart disease.
  • a reading of less than 1.0 mg/L can be indicative of a subject that has a low risk of cardiovascular disease
  • a reading of 1.0-2.9 mg/L can be indicative of a subject that has an intermediate risk of cardiovascular disease
  • a reading of CRP higher than 3.0 mg/L can be indicative of a subject that is at high risk for heart disease.
  • electrocardiograms and specialized ECGs can be used to assess the overall rhythm of the heart and weaknesses in different parts of the heart muscle in order to assess the presence of, or risk of development of, a cardiac disorder.
  • an ECG is used to measure and diagnose abnormal cardiac rhythm disorders, including but not limited to abnormal cardiac rhythms caused by damage to the conductive tissue that carries electrical signals, or abnormal rhythms caused by abnormal electrolyte levels.
  • ECGs can be used to diagnose and identify damaged heart muscle caused by myocardial infarction (MI), for example.
  • MI myocardial infarction
  • echocardiograms can be used to identify candidate subjects in the methods disclosed herein. Echocardiograms are graphic outlines of the heart's movement. High-frequency sound waves (ultrasound) provide pictures of the heart's valves and chambers, which allows the evaluation of the pumping action of the heart. In some embodiments, the echocardiogram can be used to measure the overall function of a subject's heart and/or determine the presence of many types of heart disease, including but not limited to left ventricular hypertrophy, indicative of cardiac conditions such as heart failure, aortic stenosis, aortic insufficiency, hypertension, cardiomyopathy, myocardial infarction, or the like.
  • Stress Tests can be used to identify candidates that have, or at risk of developing either a cardiac rhythm disorder, or ischemia.
  • Cardiac Catheterization can be used to identify candidate subjects in the methods disclosed herein.
  • Cardiac catheterization is an invasive imaging procedure during which a catheter (a long, narrow tube), is inserted into a blood vessel in the arm or leg, and guided to the heart with the aid of a special X-ray machine. Contrast dye is injected through the catheter, which allows for X-ray movies of the valves, coronary arteries and heart chambers to be created.
  • coronary angiograms can be used to identify subjects with, or at risk of developing, a cardiac disorder such as, for example, coronary artery disease, orthe like.
  • Electrophysiology (EP) Testing records the electrical activity and the electrical pathways of the heart. It is used to determine the cause of heart rhythm disturbances. Accordingly, in some embodiments, EP testing can be used to identify candidate subjects in the methods disclosed herein.
  • a candidate subject is identified as having or as being at risk of developing, more than one cardiac disorder.
  • the methods disclosed herein involve the identification of a subject that has heart failure, and that has, or is at risk of developing, atrial fibrillation.
  • the methods disclosed herein encompass the prevention of atrial fibrillation, e.g., in a subject that has heart failure.
  • the methods disclosed encompass the prevention or treatment of Torsade des Pointes in a subject with atrial fibrillation, or the like.
  • Embodiments of the methods disclosed herein involve the administration of a therapeutically effective amount of a composition comprising, consisting essentially of, or consisting of K201 to a subject in need thereof.
  • a "therapeutically effective amount” as used herein includes within its meaning a non-toxic but sufficient amount of a compound or composition for use in the invention to provide the desired therapeutic effect.
  • the exact amount of the composition comprising, consisting essentially of, or consisting of K201 disclosed herein required will vary from subject to subject depending on factors such as the species being treated, the age and general condition of the subject, co-morbidities, the severity of the condition being treated, the particular agent being administered and the mode of administration and so forth. Thus, it is not possible to specify an exact "effective amount”.
  • K201 is administered in an oral dosage form.
  • Oral dosage forms are desirable when compared to, for example, intravenous dosage forms, that are more invasive and often require the assistance of medical personnel. Regardless of the dosage form, however, the administration should provide a therapeutically effective amount of the active compound(s).
  • a therapeutically effective amount of K201 compositions is an amount sufficient to achieve a therapeutically effective plasma concentration of the M-II metabolite of K201 to treat an existing cardiac disorder.
  • the methods involve administering K201 to maintain a plasma level M-II above the minimal effective concentration (MEC) value.
  • the methods involve administering K201 to maintain plasma levels of K201 and/or M-II, such that the cumulative plasma levels of K.201 and M-II are effective to treat or prevent a cardiac disorder.
  • the dose will be such that the plasma levels of the active inredients, e.g., K201 and the M-II metabolite of K201 are, together, above the minimal effective concentration (MEC) value.
  • the MEC can be estimated from in vitro or in vivo data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration.
  • K201 or pharmaceutically compositions comprising, consisting essentially of, or consisting of K201, can be administered using a regimen which maintains plasma levels above the MEC of K.201 and/or M-II for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • K201, or a derivative thereof as disclosed herein can be administered parenterally, such as intramuscularlly, subcutaneously, intravenously, via intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections or the like.
  • the K201, or derivative thereof is provided orally.
  • a “therapeutically effective amount" of the compounds disclosed herein can be an amount sufficient to arrest, stop, or reverse an existing cardiac arrhythmia, such as an atrial cardiac arrhythmia, e.g., atrial fibrillation, atrial flutter, other supraventricular tachycardias, or the like, as determined using conventional diagnostic methods.
  • an atrial cardiac arrhythmia e.g., atrial fibrillation, atrial flutter, other supraventricular tachycardias, or the like, as determined using conventional diagnostic methods.
  • a "therapeutically effective amount" of the compounds disclosed herein can be an amount sufficient to stop or reverse a ventricular cardiac arrhythmia, such as ventricular tachycardia, e.g., Torsade des Pointes, catcholaminergic polymorphic ventricular tachycardia, or monomorphic ventricular tachycardia, as determined using conventional diagnostic methods.
  • a therapeutically effective amount of the compounds disclosed herein is an amount effective to prevent a cardiac rhythm disorder, such as an atrial arrhythmia or a ventricular arrhythmia, as determined using conventional diagnostic methods.
  • a "therapeutically effective amount” of a compound disclosed herein is an amount sufficient to stop, arrest, or prevent sudden cardiac death. In some embodiments, a “therapeutically effective amount” of a compound disclosed herein is an amount sufficient to stop, arrest or reverse acute and/or chronic heart failure, such as left ventricular diastolic dysfunction, left ventricular systolic dysfunction, or the like, as determined using conventional diagnostic methods. In some embodiments, a "therapeutically effective amount” of a compound disclosed herein is an amount sufficient to stop, arrest or reverse acute coronary syndrome, e.g., myocardial infarction and/or angina.
  • a "therapeutically effective amount” of a compound disclosed herein is an amount sufficient to stop, arrest or reverse hypertension, e.g., acute hypertension, chronic hypertension, catecholamine-induced hypertension, or the like, as determined by conventional diagnostic methods. In some embodiments, a “therapeutically effective amount” of a compound disclosed herein is an amount sufficient to stop, arrest or reverse pulmonary edema, as determined by conventional diagnostic methods. In some embodiments, a “therapeutically effective amount” of a compound disclosed herein is an amount sufficient to stop, arrest or reverse chronic obstructive pulmonary disease.
  • a "therapeutically effective amount” can be, for example, 0.01 ⁇ g/kg K201, 0.1 ⁇ g/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 1.5 ⁇ g/kg, 2.0 ⁇ g/kg, 2.5 ⁇ g/kg, 3.0 ⁇ g/kg, 3.5 ⁇ g/kg, 4.0 ⁇ g/kg, 4.5 ⁇ g/kg, 5.0 ⁇ g/kg, 10 ⁇ g/kg, 15 ⁇ g/kg, 20 ⁇ g/kg, 25 ⁇ g/kg, 30 ⁇ g/kg, 35 ⁇ g/kg, 40 ⁇ g/kg, 45 ⁇ g/kg, 50 ⁇ g/kg, 55 ⁇ g/kg, 60 ⁇ g/kg, 65 ⁇ g/kg, 70 ⁇ g/kg, 75 ⁇ g/kg, 80 ⁇ g/kg, 85 ⁇ g/kg, 90 ⁇ g/kg, 95 ⁇ g/kg, 100 ⁇ g/kg, 150 ⁇ g/kg,
  • the dose of K201 administered to the subject can be 0.1 mg, 1 mg, 2mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg,, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g, or more, or any amount in between.
  • the dose of K201 administered to the subject is between about 0.1 mg to 1 mg, 1 mg to 5 mg, 5 mg to 20 mg, 20 mg to 50 mg, 50 mg to 75 mg, 75 mg to 100 mg, 100 mg, to 150 mg, 150 mg to 200 mg, 200 mg to 300 mg, 300 mg, to 400 mg, 400 mg to 500 mg, 500 mg to 600 mg, 600 mg, to 700 mg, 700 mg to 1 g, or more, or any amount in between.
  • K201 in an oral dosage form results in relatively high plasma concentrations of the M-II metabolite of K201, as shown in Table 3, below.
  • metabolites of K201 e.g., the M-II metabolite
  • has antiarrhythmic properties As shown in Table 2 oral dosage forms of K201 go through significant first pass metabolism, so that administering K201 orally results in significant plasma levels of the M-II metabolite. Accordingly, some embodiments disclosed herein relate to the administration of K201 , e.g., in an oral dosage form, to achieve a combined plasma concentration K.201 and its metabolite(s), e.g., M-II, that is therapeutically effective.
  • the accompanying data demonstrate that it is possible to achieve desired therapeutic effects, i.e., treatment and/or prevention of cardiac conditions such as cardiac rhythm disorders, by designing a therapy regimen, e g , involving administering K.201 in an oral dosage form, to provide a plasma concentration of K201 and M-II effective to treat or prevent the cardiac condition.
  • a therapy regimen e g , involving administering K.201 in an oral dosage form, to provide a plasma concentration of K201 and M-II effective to treat or prevent the cardiac condition.
  • the subject is administered K201, or a composition or formulation consisting of, consisting essentially of, or comprising K201 in multiple doses.
  • the subject is administered K201 over a mutli-day period (e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, or more), according to a dosing schedule, wherein the dosing schedule requires no more than one, two, three, four, five, or six temporally-spaced doses per days.
  • the dosing schedule requires no more than two doses per day.
  • the elimination half life is used to determine the dosage intervals of K201.
  • a peak blood concentration of K201 C max
  • Tl a peak blood concentration of K201
  • T2 a minimum effective concentration
  • T3 a minimum effective concentration
  • T3 is selected such that the subject has a plasma level of K201 M-II at T3, such that either the level of M-II, or the combined plasma concentration of M-II and K201 at T3 are effective to treat or prevent a cardiac condition, such as arrhythmia.
  • the C max following administration is about 50 nM, 60 nM, 7OnM, 8OnM, 90 nM, 10OnM, 1 10 nM, 120 nM, 130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 210 nM, 220 nM, 230 nM, 240 nM, 250 nM, 260 nM, 270 nM, 280 nM, 290 nM, 300 nM, 310 nM, 320 nM, 330 nM, 340 nM, 350 nM, 360 nM, 370 nM, 380 nM, 390 nM, 400 nM, 410 nM, 420 nM, 430 nM, 440 nM, 450 nM, 460 nM, 470 nM, 480 nM,
  • the C mec of K201 and/or M-II is about 50 nM, 60 nM, 7OnM, 8OnM, 90 nM, 10OnM, 1 10 nM, 120 nM, 130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 210 nM, 220 nM, 230 nM, 240 nM, 250 nM, 260 nM, 270 nM, 280 nM, 290 nM, 300 nM, 310 nM, 320 nM, 330 nM, 340 nM, 350 nM, 360 nM, 370 nM, 380 nM, 390 nM, 400 nM, 410 nM, 420 nM, 430 nM, 440 nM, 450 nM, 460 nM, 470 nM, 400
  • Tl is reached within 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 15 min, 20 min, 30 min, 40 min 50 min, 60 min, 70 min, 80 min, 90 min, 100 min, 1 10 min, 120 min, or longer, depending on the rate and route of administration.
  • T2 is reached within 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 15 min, 20 min, 30 min, 40 min 50 min, 60 min, 70 min, 80 min, 90 min, 100 min, 1 10 min, 120 min, 130 min, 140 min, 150 min, 160 min, 170 min, 180 min, 190 min, 200 min, 210 min, 220 min, 230 min, 240 min, 250 min, 260 min, 270 min, 280 min, 290 min, 300 min, 400 min, 410 min, 420 min, 430 min, 440 min, 450 min, 460 min, 470 min, 480 min, 490 min, 500 min, 510 min, 520 min, 530 min, 540 min, 550 min, 560 min, 570 min, 580 min, 590 min, 600 min, or less, or more, or any number in between.
  • the methods include the design of a course of therapy for at least a predetermined time period, wherein the course of therapy includes the administration of multiple doses of K201.
  • the time period is equal or greater than the time period to go from peak to trough plasma concentration levels of the M-II metabolite of K201.
  • the time period is equal or great than the half life of K201 , but less than the time period to go from peak to trough plasma concentration levels of M-II.
  • the exemplary therapeutically effective amounts of K201 described herein can, in some embodiments be administered on an hourly basis, e.g., every one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three hours, or any interval in between, or on a daily basis, every two days, every three days, every four days, every five days, every six days, every week, every eight days, every nine days, every ten days, every two weeks, every month, or more or less frequently, as needed to achieve the desired therapeutic effect.
  • K201 is administered at least every 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, every 24 hours, or any interval in between, or longer.
  • the K201 is provided in an oral dosage form.
  • K201 can be provided in a single dose during the administration.
  • the subject is provided a single oral dose of K201.
  • about 2 mg/kg to 6 mg/kg or more of K201 can be provided in a single dose, for example in a continuous intravenous infusion.
  • K.201 can provided in more than one dose during the administration, for example, two, three or more doses of K201, can be provided in a single continuous intravenous infusion.
  • K201 is administered in multiple doses (i.e., more than one dose) in the methods described herein.
  • the time period between sequential doses of K201 exceeds the half life of K201 , or T2 as discussed above.
  • the time period between sequential doses of K201 greater than or equal to the elimination half time of K201.
  • K201 can be provided in a continuous infusion for a period of time of about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 1 1 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, or more.
  • K201 can be provided in a continuous infusion for a period of time of about 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours, 5.5 hours, 6 hours, or 6.5 hours, or any amount of time in between.
  • two doses of K201 can be provided in a continuous infusion over a period of about 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, or 7 hours.
  • the first dose can be provided over about 1.5 to about 2.5 hours, preferably 2 hours, and the second dose can be provided over about 3.5 hours, 4 hours, or 4.5 hours, preferably about 4 hours.
  • K201 is provided in a 1 minute infusion, a 2 minute infusion, a 3 minute infusion, a 4 minute infusion, a 5 minute infusion, a 6 minute infusion, a 7 minute infusion, an 8 minute infusion, a 9 minute infusion, a 10 minute infusion, an 1 1 minute infusion, a 12 minute infusion, a 13 minute infusion, a 14 minute infusion, a 15 minute infusion, a 16 minute infusion, a 17 minute infusion, an 18 minute infusion, a 19 minute infusion, a 20 minute infusion, a 21 minute infusion, a 22 minute infusion, a 23 minute infusion, a 24 minute infusion, a 25 minute infusion, a 26 minute infusion, a 27 minute infusion, a 28 minute infusion, a 29 minute infusion, a 30 minute infusion, or longer infusion, or any length of time in between, as described herein.
  • the methods include the administration of a therapeutically effective amount of a composition comprising K201 or a pharmaceutically acceptable salt, ester, or amide thereof to the subject, and informing the subject or a medical care worker that administration of the composition can provide antiarrhythmic effects for a period of time following administration, wherein the time period exceeds the half life of K201.
  • the term "informing" means referring to or providing published material, for example, providing an active agent with published material to a user; or presenting information orally, for example, by presentation at a seminar, conference, or other educational presentation, by conversation between a pharmaceutical sales representative and a medical care worker, or by conversation between a medical care worker and a patient; or demonstrating the intended information to a user for the purpose of comprehension.
  • a "medical care worker” means a worker in the health care field who may need or utilize information regarding an active agent, including a dosage form thereof, including information on safety, efficacy, dosing, administration, or pharmacokinetics. Examples of medical workers include physicians, pharmacists, physician's assistants, nurses, aides, caretakers (which can include family members or guardians), emergency medical workers, and veterinarians.
  • the methods involve informing the subject and/or medical care working that administration of the K201 compositions can provide antiarrhythmic effects for a period of time exceeding about 2 hours, 3 hours, four hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 1 1 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days 5 days, 6 days, a week, or more.
  • the methods include the step of designating a course of therapy that is intended to achieve treatment of a cardiac disorder, or maintenance of cardiac function (e.g., maintenance of normal sinus rhythm or the like), for at least a predetermined period, wherein the course of therapy includes administration of an a composition comprising K201, or pharmaceutically acceptable salt, ester, or amide thereof.
  • the K201 administration can be completed at least about 2 hours, 3 hours, four hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 1 1 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days 5 days, 6 days, a week, or more, or more prior to completion of the predetermined period for the course of the therapy.
  • the additional therapeutic agent(s) and K201 or a pharmaceutically acceptable salt, ester, or amide thereof can be administered nearly simultaneously.
  • K201 and the other therapeutic agent(s) are in the same administrable composition, i.e., a single tablet, pill, or capsule, or a single solution for intravenous injection, or a single drinkable solution, or a single dragee formulation or patch, contains both compounds.
  • the embodiments also include those in which each compound(s) is in a separate administrable composition, but the subject is directed to take the separate compositions nearly simultaneously, i.e., one pill is taken right after the other or that one injection of one compound is made right after the injection of another compound, etc.
  • the levels of M-II and/or K201 in a subject can be measured following administration of K201.
  • the measurement of K201 and/or M-II can be preformed using routine diagnostic methods such as HPLC or bioassays.
  • the methods described herein can include the step of measuring the presence or existence of symptoms or signs associated with the cardiac disorder, following administration of K201, or pharmaceutical composition comprising K201 to the subject.
  • the administration of K201 or a pharmaceutically acceptable salt, ester or amide thereof transforms the mammal, such that the cardiac condition is lessened, treated or prevented in the mammal.
  • the administration of K201 , or pharmaceutical composition comprising K201 causes a cessation or an amelioration of a cardiac rhythm disorder in a subject with an existing cardiac rhythm disorder, or, preserves regular sinus rhythm.
  • the subject is administered a composition that comprises, consists essentially of, or consists of, K201 or a pharmaceutically acceptable salt, ester, or amide thereof.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to a subject to which it is administered and does not abrogate the biological activity and properties of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutical salts can also be obtained by reacting a compound disclosed herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxyrnethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxyrnethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • exemplary salts include salts derived from organic acids, such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like; and salts derived from ammo acids, such as glutamic acid or aspartic acid.
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic,
  • esters refers to a chemical moiety with formula -(R) n -COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • An "amide” is a chemical moiety with formula -(R) n -C(O)NHR' or -(R) n -NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • An amide may be an amino acid or a peptide molecule attached to a compound of the embodiments disclosed herein, e.g., a K201 metabolite such as, for example M-IL.
  • Any amine, hydroxy, or carboxyl side chain on the compounds disclosed herein, or esters, or amides of the compounds disclosed herein can be esterified or amidified.
  • the procedures and specific groups to be used to achieve this end is known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.
  • administering is intended to encompass administration of a drug to a subject or patient, including administration by a third party and self- administration.
  • K201 can be provided in a pharmaceutical composition that comprises, consists essentially of, or consists of K201 and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
  • pharmaceutical composition refers to a mixture of a compound of the invention with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
  • compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • carrier defines a chemical compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the uptake of many organic compounds into the cells or tissues of an organism.
  • diot defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art.
  • One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • compositions described herein can be administered to a human subject per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s).
  • suitable carriers or excipient(s) include butylene glycol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, s thereof.
  • compositions for use in accordance with the embodiments described herein thus can be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well- known techniques, carriers, and excipients can be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
  • the agents of the invention may be formulated in aqueous solutions or lipid emulsions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination of the invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethy lcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • the formulations of the present invention may be coated with enteric polymers. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • K201 for parenteral delivery is as follows:
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for the compounds described herein is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • a common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant POLYSORBATE 80 TM , and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • VPD co-solvent system which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant POLYSORBATE 80 TM , and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80 ; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
  • salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acid or base forms.
  • compositions may, if desired be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • step (a) 5-methoxy-2nitrobenzoic acid (SIGMA Aldrich, Cat. No. 391999, St. Louis, MO), was treated with a reducing agent, in the presence of a catalyst, H 2 , Pd/C, MeOH, at room temperature, as described in U.S. Patent Application Publication No. 2004/0229871.
  • step (b) the compound formed in step (a) was treated with a diazotizing agent and a disulfide, NaNO 2 , HC1/H 2 , Na 2 S 2 .
  • the compound formed in step (b) was treated with a SOCl 2 followed by H 2 NCH 3 CH 2 Cl, H 2 NCH 2 Cl.
  • step (c) The compound formed in step (c) was reduced/cyclized by treating the compound with sodium borohydride in ethanol, as described in J. Heterocyl. Chem (1988), 25:1007 or Eur. J. Med. Chem. Chim. Ther. (1993) 28(3):213.
  • the compound formed in step (d) was treated with BH 3 or the like, to form an amine.
  • the compound formed in step (e) was treated with acryloyl chloride toluene in the presence of Na 2 Co 3 .
  • the compound formed in step (f) was oxidized with meta- chloroperbenzoic acid in dichloromethane at a low temperature.
  • step (g) was converted to M-II by treating with 4-benzylpiperidine as described in J. Am. Chem. Soc. (1957) 79:3805.
  • EXAMPLE 2 Pharmacokinetic Properties of K201
  • K.201 in the indicated amounts, was administered to the subjects via intravenous injection over 10 minutes. At 0, 3, 5, 10, 15, 30, 45 min and 1 , 2, 3, 4, 6, 8, 12, 24 hours, a blood sample was obtained from the subject and the plasma was analyzed via HPLC to determine the concentration of K201. Urine samples were obtained from subjects at 0, 2, 4, 8, 12 and 24 hours, and analyzed via HPLC for K201. The data are presented in Table 2, below.
  • K201 exhibited biphasic elimination after intravenous injection, with rapid distribution (alpha phase) followed by a slower elimination (beta phase).
  • the peak plasma K201 concentrations and the AUC (O . X) values appeared to increase in proportion to increasing dose from 10 to 500 ⁇ g/kg (Table 4).
  • drug distribution was rapid, with an average initial (alpha) half-life of 2 to 3 minutes, and mean terminal elimination half-life of about 2 hours.
  • Volume of distribution (Vss) and clearance (CL) appeared to be independent of dose, with Vss averaging about 1.3 L/kg and CL averaging approximately 0.5 L/h/kg.
  • Urinary excretion of K201 was very low, averaging 0.2% of the administered dose in all dose groups.
  • K201 was administered via the oral route in the indicated amounts. At 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 h post-dose, a blood sample was obtained from the subject and plasma was analyzed via HPLC to determine the concentration of M-II. The data are presented in Table 5, below.
  • HEK293 cells were stably transfected with the appropriate ion channel cDNA encoding the pore-forming channel subunit. Stable transfectants were selected using the G418-resistance gene incorporated into the expression plasmid. Selection pressure was maintained with G418 in the culture medium. Cells were cultured in D-MEM/F-12 (Dulbecco's Modified Eagle Medium/Nutrient Mixture F- 12) supplemented with 10% FBS, 100 U/mL penicillin G sodium, 100 ⁇ g/mL streptomycin sulfate and 500 ⁇ g/mL G418.
  • D-MEM/F-12 Dulbecco's Modified Eagle Medium/Nutrient Mixture F- 12
  • CHO cells were stably transfected with the appropriate ion channel cDNAs.
  • Cells were cultured in Ham's F-12 supplemented with 10% FBS, 100 U/mL penicillin G sodium, 100 ⁇ g/mL streptomycin sulfate, and the appropriate selection antibiotics. Before testing, cells in culture dishes were washed twice with Hank's Balanced Salt Solution, treated with trypsin, and re-suspended in the culture media (4-6 x 10 6 cells in 20 mL). Cells in suspension were allowed to recover for 10 minutes in a tissue culture incubator set at 37 0 C in a humidified 95% air/5% CO 2 atmosphere. Test Methods
  • Intracellular solution (Table 8) was loaded into the intracellular compartments of the SEALCHIPTM planar voltage clamp tool.
  • Cell suspension was pipetted into the extracellular compartments of the SEALCHIPTM planar voltage clamp tool.
  • membrane currents were recorded using dual- channel patch clamp amplifiers in the PATCHXPRESS® ion channel reader. Before digitization, the records were low-pass filtered at one-fifth of the sampling frequency.
  • Valid whole-cell recordings met the following criteria: 1) Membrane Resistance (Rm) > 200 M ⁇ ; and 2) Leak current ⁇ 25% channel current.
  • hERG current was measured using a stimulus voltage pattern consisting of a 500 ms prepulse to -4OmV (leakage subtraction), a 2-second activating pulse to +40 mV, followed by a 2-second test pulse to -40 mV.
  • the pulse patter was repeated continuously at 10 second intervals, from a holding potential of -80 mV. Peak tail current was measured during the -40 mV test pulse. Leakage current was calculated from the current amplified evoked by the prepulse and subtracted from the total membrane current record.
  • Onset and steady-state block of hNavl.5 current was measured using a double pulse pattern consisting of a hyperpolarizing conditioning pulse (-10OmV amplitude, 200 ms duration) followed immediately by a depolarizing test pulse depolarization (-15 mV amplitude, 10 ms duration), form a holding potential of -80 mV.
  • the pulse pattern was repeated at 10 second intervals. Peak and test pulse current amplitudes were measured.
  • hCayl .2 Test Procedure [0118] Onset and steady state block of hCavl .3/ ⁇ 2 channels was measured using a stimulus voltage pattern consisting of a depolarizing test pulse (duration, 200 ms; amplitude, 10 mV) at 10 second intervals from a -80 mV holding potential. Test article concentrations were applied cumulatively in ascending order without washout between applications. Peak current was measured during the step to 10 mV. 10 ⁇ M of nifedipine was added at the end of each experiment to block hCavl .2 current. Leak current was digitally subtracted from the total membrane current record. hKvLQTl/hminK Test Procedure
  • Onset and steady state block of hHCN4current was measuring using a pulse pattern with fixed amplitudes (hyperpolarization: -120 mV amplitude, for 1 second) repeated at 10 second intervals from a holding potential of -30 mV. Current amplitude was measured at the end of the step to -120 mV.
  • the hKir6.2/hSUR2A current was activated with a 5 minute application of 100 ⁇ M pinacidil. Onset and steady state block of the current was measured using a pulse patter with fixed amplitudes (hyperpolarization: -1 10 mV amplitude, for 400 ms), followed by a 1 -second ramp from -100 mV to +10 mV) repeated at 10 second intervals from a holding potential of -60 mV.. Current amplitude was measured at the end of the step to +10 mV. TABLE 8
  • [Test] is the concentration of M-II
  • IC 50 is the concentration of M-II producing half-maximal inhibition
  • N is the Hill coefficient
  • % Block is the percentage of ion channel current inhibited at each concentration of the test article.
  • K201 metabolites possess properties that render them useful in the treatment and/or prevention of cardiac disorders, such as cardiac rhythm disorders, e.g., atrial cardiac rhythm disorders or ventricular cardiac rhythm disorders, including atrial flutter, other supraventricular tachycardias, ventricular tachycardia (e.g., Torsade des Pointes, catecholaminergic polymorphic ventricular tachycardia, and monomorphic ventricular tachycardia), as well as disorders such as sudden cardiac death, acute and/or chronic heart failure, (e.g., left ventricular systolic dysfunction or left ventricular diastolic dysfunction), acute coronary syndrome, such as myocardial infarction, angina, acute and/or chronic hypertension, (e.g., catecholamine-induced hypertension), pulmonary edema, chronic obstructive pulmonary disease and the like.
  • cardiac rhythm disorders e.g., atrial cardiac rhythm disorders or ventricular cardiac rhythm disorders, including atrial flutter, other supraventricular
  • the anesthetized dog model is a standard model for cardiovascular pharmacology investigations. Accordingly, anesthetized mongrel dogs were used, as described below, to determine the dose dependent increase in atrial effective refractory period (AERP) of K201 metabolite M-II and corresponding plasma levels of M-II, and to determine the effects of M-II on the surface ECG at designated dose levels.
  • AERP atrial effective refractory period
  • test article dosing formulations were administered intravenously to anesthetized mongrel dogs as shown in Table 21. TABLE 21
  • Lidocaine 2% was not used during intubation as the animals did not present signs of reflexes. The following parameters were regularly monitored in order to ensure proper ventilation of the animals but will not be reported: SpO 2 , inspiratory and expiratory CO 2 , inspiratory O 2 and respiratory rate.
  • Each formulation was prepared by dissolving the appropriate amount of Sorbitol into 2/3 of the final volume of Sterile Water for Injection USP under continuous stirring for 5 minutes or until the solution was clear.
  • the formulation's pH was adjusted under continuous stirring using a citric acid monohydrate (with an approximate ratio of 0.34 mg/mL of solution), to reach a pH in the range of 3.0 to 4.0.
  • the appropriate amount of test article powder was then weighed (2 mg M-II citrate salt/mL) and added into the solution.
  • the preparation was mixed until completely dissolved (using a magnetic stir plate) and the pH was recorded.
  • the pH of the formulation was adjusted using a solution of O. IN NaOH, to reach a pH of 3.25 ⁇ 0.1.
  • the preparation was then made up to the final volume with Sterile Water for Injection USP in order to reach the required concentration.
  • the final pH was then recorded as 3.00 to 3.30.
  • the formulations were filtered through a 0.2211m Polyethersulphone (PES) filter into an amber glass vial, or a clear glass vial covered with aluminum foil.
  • PES Polyethersulphone
  • Administration of M-II [0158] Each dose was administered intravenously as an infusion consisting of an initial infusion of 0.3 mg/kg/min for 2 minutes followed by 0.03 mg/kg/min for 30 minutes via the left saphenous vein.
  • ECG waveforms were monitored and recorded continuously using the Dataquest ART 3.01 Telemetry system via a transmitter (TL1OM3-D70-EEE) connected using external leads. Average values for lead II were calculated over 5 seconds due to pacing. The QT interval was corrected for heart rate changes using the Fredericia's and Van de Water's formulas.
  • a programmable stimulator (Caltronics Inc.) connected to pacing cables was used for atrial pacing. Initially, the right and left atrial diastolic pacing threshold were determined at 2 msec pulse duration, by decrementing pulse amplitude (mA) gradually until consistent loss of atrial capture was observed. Subsequently, the pulse amplitude was increased to approximately twice this value. To determine atrial effective refractory period (AERP), pacing from right and left atrial epicardial bipolar electrodes was done sequentially at basic drive cycle lengths (S 1 S 1) of 360, 300, and 200 msec for eight (8) beats.
  • S 1 S 1 S 1 basic drive cycle lengths
  • AERP a premature atrial stimuli
  • S1S2 a premature atrial stimuli
  • AERP was defined as the longest S1S2 interval that did not produce atrial capture. Similar measurements were performed to determine the left-ventricular ERP at an SlSl of 300 ms. Also, inter-atrial conduction time was used to provide an estimate of atrial conduction velocity since the distance between electrodes was constant but unknown. Inter-atrial conduction time was determined once during each drive cycle (SlSl 360, 300 and 200 msec) by measuring the stimulus to contralateral local atrial electrocardiogram interval.
  • AERP and VERP measurements are shown in Figures 8A-8D and Figure 9.
  • the K201 metabolite M-II increased atrial ERP with a slight reverse use-dependency. The significant effects lasted more than 2 and 4 hours in the left atrium ( Figures 8A-8B) and right atrium ( Figures 8C-8D), respectively.
  • the K201 metabolite M-II did not affect left ventricular ERP ( Figure 9).
  • Conduction time measurements are depicted graphically in Figures 10A-10B.
  • the K201 metabolite M-II did not affect intra-atrial conduction time. Blood pressure measurements are depicted graphically in Figures 1 IA-I IB.
  • Venous blood samples ( ⁇ 1.3 mL/sample) were collected from the left jugular or left femoral at the following timepoints: [0166] o Pre-Rx
  • M-II produced clear atrial ERP increases that were important in both atria. The increases were substantial and had the time course expected for a direct drug action. These changes would be expected to translate into antiarrhythmic actions against reentrant atrial arrhythmias, especially AF. The drug had no discernible effects on ventricular ERP or interatrial conduction time.
  • a subject presents with atrial fibrillation to the hospital, physician's office or clinic.
  • the subject is administered 2 mg/kg to 6 mg/kg mg K201 via intravenous injection over 10 minutes.
  • the subject's cardiac rhythm is monitored.
  • the subject receives one or more sequential oral doses of K201 in order to maintain a steady state plasma concentration of M-II.
  • the time between the sequential doses of K201 vary from 5 hours to 12 hours.
  • a subject with congestive heart failure present with atrial fibrillation to the hospital, physician's office or clinic.
  • the subject is administered 2 mg/kg to 6 mg/kg K201 via intravenous injection over 10 minutes.
  • the subject's cardiac rhythm is monitored.
  • the subject receives one or more sequential oral doses of K201 in order to maintain a steady state plasma concentration of M-II.
  • the time between the sequential doses of K201 vary from 5 hours to 12 hours.
  • the atrial fibrillation subsides or ceases following administration of K201.
  • a subject presents with Torsade des Pointes to the hospital, physician's office or clinic.
  • the subject is administered 2 mg/kg to 6 mg/kg K201 via intravenous injection.
  • the subject's sinus rhythm is monitored.
  • the subject receives one or more sequential doses of K201 in order to maintain a steady state plasma concentration of M-II.
  • the time between the sequential doses of K201 vary from 5 hours to 12 hours.
  • a subject presents with CHF arising from an acute injury to the heart, such as a myocardial infarction.
  • the subject can exhibit abnormalities in the left ventricle, as evidenced by echocardiogram.
  • the subject is administered 2 mg/kg to 6 mg/kg K201 via intravenous injection.
  • the subject's sinus rhythm and ejection fractions are monitored.
  • the subject receives one or more sequential doses of K201 in order to maintain a steady state plasma concentration of M-II.
  • the time between the sequential doses of K201 vary from 5 hours to 12 hours.
  • One or more of the symptoms of heart failure improves following administration of K201.
  • a subject presents with diastolic heart failure.
  • the subject is administered 2 to 6 mg K201 via intravenous injection.
  • the subject's sinus rhythm and ejection fractions are monitored.
  • the subject receives one or more sequential doses of K201 in order to maintain a steady state plasma concentration of M-II.
  • the time between the sequential doses of K201 vary from 5 hours to 12 hours.
  • One or more of the symptoms of diastolic heart failure improves following administration of K201.

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Abstract

Provided herein are methods of treating and preventing cardiac arrhythmias and other cardiac disorder in a subject in need thereof, comprising providing a therapeutically effective amount of K201 or a pharmaceutically acceptable salt, ester, or amide thereof, and informing the patient or medical care worker that administration can provide antiarrhythmic effects for a period of time following administration of the composition, wherein the time period is at least about four hours. Also provided herein are methods of treating subject having or at risk of developing cardiac arrhythmias that involve designing a course of therapy that is intended to achieve antiarrhythmic effects for at least a predetermined period, wherein the course of therapy includes the administration of more than one dose of a therapeutically effective amount of K201 or a pharmaceutically acceptable salt, ester, or amide thereof, and wherein when the time period between the sequential doses of K201 exceeds the time period for which a therapeutically adequate plasma level of K201 exists.

Description

IMPROVED METHODS OF ADMINISTRATION OF K201 (JTV-519) (4-[3-{l-(4-
BENZYL)PIPERIDINYLJPROPIONYL]-T-METHOXY 2, 3, 4, 5-TETRAHYDRO-l,4-
BENZOTHIAZEPINE MONOHYDROCHLORIDE)
BACKGROUND OF THE INVENTION Field of the Invention
[0001] The embodiments disclosed herein relate to methods of treating and/or preventing cardiac disorders using a benzothiazepine derivative. Description of the Related Art
[0002] Currently available treatments for cardiac rhythm disorders, such as antiarrhythmics, are fraught with problems. Atrial flutter and/or atrial fibrillation (AF) are the most commonly sustained cardiac arrhythmias in clinical practice, and are likely to increase in prevalence with the aging of the population. Currently, AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases and causes more than 80,000 strokes each year in the United States. While AF is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism. Currently available Class I and Class III antiarrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects, including ventricular proarrhythmia.
[0003] Although various therapeutic agents for cardiac disorders are now available on the market, those having both satisfactory efficacy and a high margin of safety have not been approved. For example, antiarrhythmic agents of Class I, according to the classification scheme of Vaughan- Williams (''Classification of antiarrhythmic drugs," Cardiac Arrhythmias, edited by: E. Sandoe, E. Flensted-Jensen, K. Olesen; Sweden, Astra, Sodertalje, pp 449-472 (1981)), which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) are inadequate for preventing cardiac disorders such as ventricular fibrillation because they shorten the wavelength of the cardiac action potential, thereby favoring re-entry. In addition, they have problems regarding safety, as they depress myocardial contractility and have a tendency to induce arrhythmias due to an inhibition of impulse conduction. The serious adverse side effects resulted in the termination of the CAST (coronary artery suppression trial) study, because the Class I antagonists had a higher mortality than placebo controls. Class II and Class IV antiarrhythmics, while having a higher safety margin than the Class I agents, are also of limited therapeutic value. In particular, β-adrenergenic receptor blockers and calcium channel (lea) antagonists, which belong to Class II and Class IV, respectively, are of limited therapeutic values as their therapeutic effects is are limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease.
[0004] Class III antiarrhythmic agents function by increasing myocardial refractoriness via a selective prolongation of cardiac action potential duration (APD). Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e., Na+ or Ca2+ currents; hereinafter I^and Ica, respectively) or by reducing outward repolarizing potassium K+ currents. The delayed rectifier (IK) K+ current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (It0) and inward rectifier (IKi) K+ currents are responsible for the rapid initial and terminal phases of repolarization, respectively. Cellular electrophysiologic studies have demonstrated that IK consists of two pharmacologically and kinetically distinct K+ current subtypes, Iκr (rapidly activating and deactivating and Iκs (slowly activating and deactivating). (Sanguinetti and Jurkiewicz, "Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by Class III antiarrhythmic agents", J Gen. Physiol 96: 195-215 (1990)). Iκr is the product of the human ether-a-go-go gene (hERG). Expression of hERG cDNA in cell lines leads to production of a hERG current which is almost identical to Iκr (Curran et al., "A molecular basis for cardiac arrhythmia: hERG mutations cause long QT syndrome," Cell 80(5):795-803 (1995)).
[0005] With the exception of amiodarone and ibutilide, which are blockers of IKS and an inducer of the slow Na current, respectively, Class III antiarrhythmic agents including d-sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and methanesulfonamide- N-[ 1 '-6-cyano- 1 ,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro-4-hydroxyspiro[2H- 1 - benzopyran-2,4'-piperidin]-6-yl], (+)-, monochloride A-499) predominantly, if not exclusively, block Iκr- Amiodarone also blocks INa and Ica, effects thyroid function, is as a nonspecific adrenergic blocker, acts as an inhibitor of the enzyme phospholipase, and causes pulmonary fibrosis (Nademanee, K "The Amiodarone Odessey". J. Am. Coll. Cardiol. 20:1063-1065 (1992)).
[0006] Since Iκr blockers increase APD and refractoriness both in atria and ventricle without affecting conduction per se, theoretically they represent potential useful agents for the treatment of arrhythmias-like AF and VF. These agents have a liability, however, in that they have an enhanced risk of proarrhythmia at slow heart rates. For example, Torsade de Pointes, a specific type of polymorphic ventricular tachycardia which is commonly associated with excessive prolongation of the electrocardigraphic QT interval, hence termed "acquired long QT syndrome", has been observed when these compounds are utilized (Roden, D. M. "Current Status of Class III Antiarrhythmic Drug Therapy", Am J. Cardiol, 72:44B-49B (1993)). The exaggerated effect at slow heart rates has been termed "reverse frequency-dependence" and is in contrast to frequency-independent or frequency- dependent actions.
[0007] The slowly activating component of the delayed rectifier (Iκs) potentially overcomes some of the limitations of Iκr blockers associated with ventricular arrhythmias. Because of its slow activation kinetics, however, the role of Iκs in atrial repolarization may be limited due to the relatively short APD of the atrium. Consequently, although IKS blockers may provide distinct advantage in the case of ventricular arrhythmias, their ability to affect supra-ventricular tachyarrhythmias (SVT) is considered to be minimal.
[0008] Another major defect or limitation of most currently available Class III antiarrhythmic agents is that their effect increases or becomes more manifest at or during bradycardia or slow heart rates, and this contributes to their potential for proarrhythmia. On the other hand, during tachycardia or the conditions for which these agents or drugs are intended and most needed, they lose most of their effect. This loss or diminishment of effect at fast heart rates has been termed "reverse use-dependence" (Hondeghem and Snyders, "Class HI antiarrhythmic agents have a lot of potential but a long way to go: Reduced effectiveness and dangers of reverse use dependence", Circulation 81 :686-690 (1990); Sadanaga et al., "Clinical evaluation of the use-dependent QRS prolongation and the reverse use-dependent QT prolongation of class III antiarrhythmic agents and their value in predicting efficiency" Amer. Heart Journal 126:114-121 (1993)), or "reverse rate- dependence" (Bretano, "Rate dependence of class HI actions in the heart", Fundam. Clin. Pharmacol. 7:51-59 (1993); Jurkiewicz and Sanguinetti, "Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent: Specific block of rapidly activating delayed rectifier K+ current by dofetilide", Circ. Res. 72:75-83 (1993)).
[0009] In view of the foregoing, it is clear the there is a need for new and improved courses of therapy for the treatment of cardiac disorders, including but not limited to cardiac rhythm disorders.
SUMMARY OF THE INVENTION
[0010] Embodiments disclosed herein relate to methods of preventing and/or treating a cardiac disorder in a subject with K201 or a pharmaceutically acceptable salt, ester, or amide thereof. In the embodiments disclosed herein, the K201 dosing regimen is calculated based upon the pharmacokinetics of a metabolite of K201 , e.g., the M-II metabolite, as the M-II metabolite has antiarrhythmic properties, as disclosed herein.
[0011] Accordingly, provided herein are methods of treating a subject by administering multiple doses of K201 over a multi-day period to a subject suffering from or at risk of cardiac arrhythmia. In some embodiments the administration of K201 can be according to a dosing schedule, wherein the dosing schedule requires no more than three temporally-spaced doses per day. For example, in some embodiments, the dosing schedule requires no more than two doses per day. In some embodiments, the K201 can be administered in an oral dosage form. In some embodiments, the subject can have congestive heart failure, e.g., either systolic and/or diastolic heart failure.
[0012] Also provide are methods of treating a subject that is suffering from or at risk of arrhythmia, by providing a formulation of K.201 for administration to the subject, wherein upon administration to the subject, the formulation provides a peak blood concentration of K201 (Cmax) at a first time Tl (measured from the administration), after which the blood concentration of K201 decreases to a minimum effective concentration (Cmec) at a second time T2 (measured from the administration). In some embodiments, the subject is administered multiple, temporally spaced doses of the K201 formulation over multiple days, according to a dosing schedule. In some embodiments, the spacing between at least some doses is an interval T3, wherein T3 is greater than T2. In some embodiments, T3 can be selected such that the subject has a blood level of the K201 metabolite Mil at T3 such that either the level of Mil or the combined levels of Mil and K201 at T3 are effective to treat or prevent arrhythmia in the subject. In some embodiments, the subject can have heart failure, e.g., systolic and/or diastolic heart failure.
[0013] Also provided herein is a method of treating or preventing a cardiac arrhythmia in a subject in need thereof, by providing a therapeutically effective amount of K201 or a pharmaceutically acceptable salt, ester, or amide thereof to a subject identified as suffering from or being at risk of cardiac arrhythmia, and informing the subject or medical care worker that administration can provide antiarrhythmic effects for a period of time following administration of the composition, wherein the time period exceeds the half life of K201. In some embodiments, the time period is at least six hours. For example, in some embodiments, the subject or medical care worker can be informed that the antiarrhythmic effects can last for a time period, wherein the time period exceeds the half life of K201, or for a time period that is longer than the time period between the peak and trough of the plasma levels of K201, or for a time period that exceeds the time period for which a therapeutically adequate plasma level of K201 exists in a subject following administration of K201. In some embodiments, the time period can be at least six hours, e.g., seven hours, eight hours, nine hours, ten hours, eleven hours, twelve hours, or more. Preferably, the time period is twelve hours or greater. K201 can be administered to the patient. In some embodiments, the subject can have heart failure, e.g., systolic and/or diastolic heart failure.
[0014] Also provided herein are methods for treating a subject that involve designing a course of therapy that is intended to achieve antiarrhythmic effects for at least a predetermined period, wherein the course of therapy includes the administration of more than one dose of a therapeutically effective amount of K201 or a pharmaceutically acceptable salt, ester, or amide thereof, and wherein when the time period between the sequential doses of K201 exceeds the half-life of K201; and administering K201 to the subject according to the designed course of therapy, wherein the subject has or is at risk of developing a cardiac arrhythmia. In some embodiments, the subject has congestive heart failure, e.g., systolic heart failure and or diastolic heart failure. In some embodiments, the time period exceeds the half life of K201, or for a time period that is longer than the time period between the peak and trough of the plasma levels of K201, or for a time period that exceeds the time period for which a therapeutically adequate plasma level of K201 exists in a subject following administration of K201. In some embodiments, the time period can be at least six hours, e.g., seven hours, eight hours, nine hours, ten hours, eleven hours, twelve hours, or more.
[0015] Some embodiments provide methods of treating or preventing a cardiac disorder in a subject in need thereof by providing a therapeutically effective amount of K201 or a pharmaceutically acceptable salt, ester, or amide thereof to a subject having or at risk of a cardiac disorder, informing the subject or medical care worker that administration can provide antiarrhythmic effects for a period of time following administration of the composition, wherein the time period exceeds the half life of K201; and administering the K201 to the subject. In some embodiments, the subject has congestive heart failure, e.g., systolic heart failure and or diastolic heart failure. In some embodiments, the time period exceeds the half life of K.201, or for a time period that is longer than the time period between the peak and trough of the plasma levels of K201, or for a time period that exceeds the time period for which a therapeutically adequate plasma level of K201 exists in a subject following administration of K201. In some embodiments, the time period can be at least six hours, e.g., seven hours, eight hours, nine hours, ten hours, eleven hours, twelve hours, or more. In some embodiments, the cardiac disorder can be an atrial cardiac rhythm disorder selected from the group consisting of atrial fibrillation, atrial flutter, or other supraventricular tachycardia. For example, in some embodiments, the cardiac disorder can be ventricular tachycardia, ventricular fibrillation, Torsades des Pointes, catecholaminergic polymorphic ventricular tachycardia, monomorphic ventricular tachycardia, sudden cardiac death, acute and/or chronic cardiomyopathy, acute coronary syndrome, e.g., myocardial infarction or angina, acute and/or chronic hypertension., acute and/or chronic hypertension is catecholamine-induced hypertension, pulmonary edema, chronic obstructive pulmonary disease, or the like. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 is a graph of the concentration-response of the K201 metabolite M-II on the hERG potassium channel, as tested as described in Example 4.
[0017] Figure 2 is a graph of the concentration-response of the K201 metabolite M-II on the hNavl .5 sodium channel, as tested as described in Example 4.
[0019] Figure3 is a graph of the concentration-response of the K201 metabolite M-II on the hKvl .5 potassium channel, as tested as described in Example 4.
[0020] Figure 4 is a graph of the concentration-response of the K201 metabolite M-II on the L-type calcium channels (hCavl.2), as tested as described in Example 4.
[0021] Figure 5 is a graph of the concentration-response of the K201 metabolite M-II on the T-type calcium channels (hCav3.2), as tested as described in Example 4.
[0022] Figure 6 is a graph of the concentration-response of the K201 metabolite M-II on the hKir3.1/3.4 potassium channel, as tested as described in Example 4.
[0023] Figure 7 is a graph of the concentration-response of the K201 metabolite M-II on the hKir6.2/SUR2A potassium channels, as tested as described in Example 4.
[0024] Figures 8A-8B are graphs showing the effect of the K201 metabolite M-II on the right atrial effective refractory period following administration, expressed in the ms (Figure 8A), or as a % increase from baseline (BL) (Figure 8B).
[0025] Figures 8C-8D are graphs showing the effect of the K201 metabolite M-II on the left atrial effective refractory period following administration, expressed in the ms (Figure 8C), or as a % increase from baseline (BL) (Figure 8D).
[0026] Figure 9 is a graph showing the effect of the K201 metabolite M-II on the left ventricular effective refractory period following administration, expressed in the ms.
[0027] Figures 10A-10B are graphs showing the effect of administration of the K201 metabolite M-II on inter-atrial conduction time, from the left atrium to right atrium (Figure 10A) and from the right atrium to the left atrium (Figure 10B).
[0028] Figures 11A-11B are graphs showing the effect of administration of the K.201 metabolite M-II on systolic, diastolic, and mean blood pressure, either before the measurement (Figure HA), or after the measurements of atrial and ventricular effective refractory periods and conduction times (Figure HB). [0029] Figures 12A-12B are graphs showing the length of sinus cycle (in ms) over time, following infusion of the K201 metabolite M-II, either before the measurement (Figure 12A), or after the measurements of atrial and ventricular effective refractory periods and conduction times (Figure 12B).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0030] K201 is a compound that has both in vitro and in vivo antiarrhythmic properties and can be used for treatment of arrhythmias in both the short term (termination of arrhythmia) and chronic settings (prevention of arrhythmia, or maintenance of sinus rhythm).
[0031] As demonstrated herein, K201 is rapidly metabolized such that even relatively high doses, given relatively frequently, would not result in therapeutically adequate plasma levels of K201.
[0032] K201 is metabolized via cytochrome P450 isoforms CYP 3A4 and 2D6. The structure of K201 and its metabolites are shown in Table 1, below:
TABLE 1
Figure imgf000009_0001
Figure imgf000010_0001
[0033] The embodiments disclosed herein are based, in part, on the surprising discovery that metabolites of K201, including M-II, have a blocking effect on cardiac ion channels as shown in the Examples below. As such, the data demonstrate that M-II, as well as K201 , is useful in the treatment and prevention of cardiac diseases and disorders, including cardiac arrhythmias. Accordingly, described herein are methods of administration of K201 to achieve desired antiarrhythmic effects at a frequency and dose based upon the elimination pharmacokinetic properties of the M-II metabolite. Specifically, disclosed herein are methods that involve administration of K201 less frequently than necessary to maintain a therapeutically effective concentration of K201 in plasma, while maintaining a therapeutically effective plasma concentration of M-II to maintain a continuous antiarrhythmic effect in a subject in need thereof.
[0034] An ideal dosage regimen for therapeutics is that by which an acceptable therapeutic concentration of drug at the site(s) of action is attained quickly and then is maintained constant, and above a minimal effective concentration (MEC) for the duration of the treatment. Ideally, the dose size and frequency of administration are designed to give a prompt "steady-state" plasma concentration of a drug.
[0035] Accordingly, the embodiments provided herein relate to methods of treating or preventing a cardiac disease or disorder in a subject. As used herein, the term "cardiac disorder," includes, but is not limited to, disorders such as cardiac rhythm disorders, such as atrial cardiac rhythm disorders or ventricular cardiac rhythm disorders. Exemplary atrial cardiac rhythm disorders include atrial fibrillation, atrial flutter, other supraventricular tachycardias, and the like. Exemplary ventricular cardiac disorders include, but are not limited to ventricular tachycardia, e.g., Torsade des Pointes, catecholaminergic polymorphic ventricular tachycardia, and monomorphic ventricular tachycardia. The term "cardiac disorder" also encompasses conditions such as sudden cardiac death, acute and/or chronic heart failure, e.g., left ventricular systolic dysfunction or left ventricular diastolic dysfunction. Other exemplary cardiac disorders include, but are not limited to acute coronary syndrome, such as myocardial infarction, angina, or the like, or acute and/or chronic hypertension, e.g., catecholamine-induced hypertension. Still other exemplary cardiac disorders include but are not limited to pulmonary edema, chronic obstructive pulmonary disease and the like. Preferred embodiments relate to the prevention or treatment of atrial fibrillation, e.g., in a subject that has heart failure, or, in other embodiments, in a subject that does not have heart failure.
[0036] The terms "subject," "patient" or "individual" as used herein refer to a vertebrate, preferably a mammal, more preferably a human. "Mammal" can refer to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as, for example, horses, sheep, cows, pigs, dogs, cats, etc. Preferably, the mammal is human.
[0037] In some embodiments described herein, the subject can be identified a "candidate" for a cardiac disorder. A "candidate" for a cardiac disorder is a subject who is known to be, or who is believed to be, or is suspected of being at risk for developing a cardiac disorder, or who is known to have, believed to have, or is suspected of having an existing cardiac disorder.
[0038] Those skilled in the art will appreciate that any routine diagnostic technique, or any combination of techniques, can be used to identify a subject that is a candidate for a cardiac disorder. By way of example, in some embodiments, the rate and regularity of a subject's heart are assessed by checking the subject's pulse, measuring the subject's systolic blood pressure and/or the subject's diastolic blood pressure. [0039] In some embodiments, blood tests, e.g., measuring a subject's serum cholesterol, high density lipoproteins, low density lipoproteins and triglycerides, as well as other markers indicative of heart disease, are used to identify candidate subjects. By way of example, the C - reactive protein (CRP) testing, for instance can be used to determine whether a subject is at risk of developing a cardiac disorder, such as heart disease. For example, a reading of less than 1.0 mg/L can be indicative of a subject that has a low risk of cardiovascular disease, a reading of 1.0-2.9 mg/L can be indicative of a subject that has an intermediate risk of cardiovascular disease, and a reading of CRP higher than 3.0 mg/L, can be indicative of a subject that is at high risk for heart disease.
[0040] In some embodiments, electrocardiograms and specialized ECGs can be used to assess the overall rhythm of the heart and weaknesses in different parts of the heart muscle in order to assess the presence of, or risk of development of, a cardiac disorder. For example, in some embodiments, an ECG is used to measure and diagnose abnormal cardiac rhythm disorders, including but not limited to abnormal cardiac rhythms caused by damage to the conductive tissue that carries electrical signals, or abnormal rhythms caused by abnormal electrolyte levels. In some embodiments, ECGs can be used to diagnose and identify damaged heart muscle caused by myocardial infarction (MI), for example.
[0041] In some embodiments, echocardiograms can be used to identify candidate subjects in the methods disclosed herein. Echocardiograms are graphic outlines of the heart's movement. High-frequency sound waves (ultrasound) provide pictures of the heart's valves and chambers, which allows the evaluation of the pumping action of the heart. In some embodiments, the echocardiogram can be used to measure the overall function of a subject's heart and/or determine the presence of many types of heart disease, including but not limited to left ventricular hypertrophy, indicative of cardiac conditions such as heart failure, aortic stenosis, aortic insufficiency, hypertension, cardiomyopathy, myocardial infarction, or the like.
[0042] In some embodiments, Stress Tests can be used to identify candidates that have, or at risk of developing either a cardiac rhythm disorder, or ischemia.
[0043] In some embodiments, Cardiac Catheterization (coronary angiogram) can be used to identify candidate subjects in the methods disclosed herein. Cardiac catheterization is an invasive imaging procedure during which a catheter (a long, narrow tube), is inserted into a blood vessel in the arm or leg, and guided to the heart with the aid of a special X-ray machine. Contrast dye is injected through the catheter, which allows for X-ray movies of the valves, coronary arteries and heart chambers to be created. Accordingly, coronary angiograms can be used to identify subjects with, or at risk of developing, a cardiac disorder such as, for example, coronary artery disease, orthe like.
[0044] Electrophysiology (EP) Testing records the electrical activity and the electrical pathways of the heart. It is used to determine the cause of heart rhythm disturbances. Accordingly, in some embodiments, EP testing can be used to identify candidate subjects in the methods disclosed herein.
[0045] In some embodiments, a candidate subject is identified as having or as being at risk of developing, more than one cardiac disorder. For example, in some embodiments, the methods disclosed herein involve the identification of a subject that has heart failure, and that has, or is at risk of developing, atrial fibrillation. As such, the methods disclosed herein encompass the prevention of atrial fibrillation, e.g., in a subject that has heart failure. Likewise, the methods disclosed encompass the prevention or treatment of Torsade des Pointes in a subject with atrial fibrillation, or the like.
[0046] Embodiments of the methods disclosed herein involve the administration of a therapeutically effective amount of a composition comprising, consisting essentially of, or consisting of K201 to a subject in need thereof. A "therapeutically effective amount" as used herein includes within its meaning a non-toxic but sufficient amount of a compound or composition for use in the invention to provide the desired therapeutic effect. The exact amount of the composition comprising, consisting essentially of, or consisting of K201 disclosed herein required will vary from subject to subject depending on factors such as the species being treated, the age and general condition of the subject, co-morbidities, the severity of the condition being treated, the particular agent being administered and the mode of administration and so forth. Thus, it is not possible to specify an exact "effective amount". However, for any given case, an appropriate "effective amount" may be determined by one of ordinary skill in the art using only routine methods. [0047] In some embodiments, K201 is administered in an oral dosage form. Oral dosage forms are desirable when compared to, for example, intravenous dosage forms, that are more invasive and often require the assistance of medical personnel. Regardless of the dosage form, however, the administration should provide a therapeutically effective amount of the active compound(s). For example, in some embodiments, a therapeutically effective amount of K201 compositions is an amount sufficient to achieve a therapeutically effective plasma concentration of the M-II metabolite of K201 to treat an existing cardiac disorder. For example, in some embodiments, the methods involve administering K201 to maintain a plasma level M-II above the minimal effective concentration (MEC) value. In some embodiments, the methods involve administering K201 to maintain plasma levels of K201 and/or M-II, such that the cumulative plasma levels of K.201 and M-II are effective to treat or prevent a cardiac disorder. For example, in some embodiments, the dose will be such that the plasma levels of the active inredients, e.g., K201 and the M-II metabolite of K201 are, together, above the minimal effective concentration (MEC) value. The MEC can be estimated from in vitro or in vivo data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. In some embodiments, K201, or pharmaceutically compositions comprising, consisting essentially of, or consisting of K201, can be administered using a regimen which maintains plasma levels above the MEC of K.201 and/or M-II for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
[0048] In some embodiments, K201, or a derivative thereof as disclosed herein can be administered parenterally, such as intramuscularlly, subcutaneously, intravenously, via intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections or the like. Preferably, the K201, or derivative thereof is provided orally.
[0049] By way of example, a "therapeutically effective amount" of the compounds disclosed herein can be an amount sufficient to arrest, stop, or reverse an existing cardiac arrhythmia, such as an atrial cardiac arrhythmia, e.g., atrial fibrillation, atrial flutter, other supraventricular tachycardias, or the like, as determined using conventional diagnostic methods. In some embodiments, a "therapeutically effective amount" of the compounds disclosed herein can be an amount sufficient to stop or reverse a ventricular cardiac arrhythmia, such as ventricular tachycardia, e.g., Torsade des Pointes, catcholaminergic polymorphic ventricular tachycardia, or monomorphic ventricular tachycardia, as determined using conventional diagnostic methods. In some embodiments, a therapeutically effective amount of the compounds disclosed herein is an amount effective to prevent a cardiac rhythm disorder, such as an atrial arrhythmia or a ventricular arrhythmia, as determined using conventional diagnostic methods.
[0050] In some embodiments, a "therapeutically effective amount" of a compound disclosed herein is an amount sufficient to stop, arrest, or prevent sudden cardiac death. In some embodiments, a "therapeutically effective amount" of a compound disclosed herein is an amount sufficient to stop, arrest or reverse acute and/or chronic heart failure, such as left ventricular diastolic dysfunction, left ventricular systolic dysfunction, or the like, as determined using conventional diagnostic methods. In some embodiments, a "therapeutically effective amount" of a compound disclosed herein is an amount sufficient to stop, arrest or reverse acute coronary syndrome, e.g., myocardial infarction and/or angina. In some embodiments, a "therapeutically effective amount" of a compound disclosed herein is an amount sufficient to stop, arrest or reverse hypertension, e.g., acute hypertension, chronic hypertension, catecholamine-induced hypertension, or the like, as determined by conventional diagnostic methods. In some embodiments, a "therapeutically effective amount" of a compound disclosed herein is an amount sufficient to stop, arrest or reverse pulmonary edema, as determined by conventional diagnostic methods. In some embodiments, a "therapeutically effective amount" of a compound disclosed herein is an amount sufficient to stop, arrest or reverse chronic obstructive pulmonary disease.
[0051] By way of example, a "therapeutically effective amount" can be, for example, 0.01 μg/kg K201, 0.1 μg/kg, 0.5 μg/kg, 1 μg/kg, 1.5 μg/kg, 2.0 μg/kg, 2.5 μg/kg, 3.0 μg/kg, 3.5 μg/kg, 4.0 μg/kg, 4.5 μg/kg, 5.0 μg/kg, 10 μg/kg, 15 μg/kg, 20 μg/kg, 25 μg/kg, 30 μg/kg, 35 μg/kg, 40 μg/kg, 45 μg/kg, 50 μg/kg, 55 μg/kg, 60 μg/kg, 65 μg/kg, 70 μg/kg, 75 μg/kg, 80 μg/kg, 85 μg/kg, 90 μg/kg, 95 μg/kg, 100 μg/kg, 150 μg/kg, 200 μg/kg, 250 μg/kg, 300 μg/kg, 350 μg/kg, 400 μg/kg, 450 μg/kg, 500 μg/kg, 550 μg/kg, 600 μg/kg, 650 μg/kg, 700 μg/kg, 750 μg/kg, 80 μg/kg 0, 850 μg/kg, 900 μg/kg, 1 mg/kg, l .Smg.kg, 2.0 mg/kg, 2.5 mg/kg, 3 mg/kg, 4.0mg/kg, 5.0 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 550 mg/kg, 600 mg/kg, 650 mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg, 950 mg/kg, lg/kg, 5 g/kg, 10 g/kg, or more, or any fraction in between, of K201/kg. Accordingly, in some embodiments, the dose of K201 administered to the subject can be 0.1 mg, 1 mg, 2mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg,, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g, or more, or any amount in between. Preferably, the dose of K201 administered to the subject is between about 0.1 mg to 1 mg, 1 mg to 5 mg, 5 mg to 20 mg, 20 mg to 50 mg, 50 mg to 75 mg, 75 mg to 100 mg, 100 mg, to 150 mg, 150 mg to 200 mg, 200 mg to 300 mg, 300 mg, to 400 mg, 400 mg to 500 mg, 500 mg to 600 mg, 600 mg, to 700 mg, 700 mg to 1 g, or more, or any amount in between.
[0052] As shown in Table 2 below, providing K201 in an oral dosage form results in relatively low plasma concentrations of K201. This is believed to be the result of first-pass metabolism of K201.
TABLE 2
I
Figure imgf000017_0001
[0053] By contrast, providing K201 in an oral dosage form results in relatively high plasma concentrations of the M-II metabolite of K201, as shown in Table 3, below.
TABLE 3
I ψ
Figure imgf000019_0001
[0054] The data provided in Table 3 demonstrates that administration of K.201 using an oral dosage form to achieve a minimal effective plasma concentration of K201 is problematic, inasmuch as the oral dosage form is rapidly metabolized, and reasonable doses of K201 do not provide therapeutically adequate plasma levels of K201. Accordingly, due to the low plasma levels of K201 following administration of an oral dosage form containing 810 mg of K201, the skilled artisan would reasonably conclude that even relatively large oral dosage forms are inadequate to achieve beneficial therapeutic effects.
[0055] As discussed in more detail below, Applicants have made the surprising discovery that metabolites of K201 , e.g., the M-II metabolite, has antiarrhythmic properties. As shown in Table 2 oral dosage forms of K201 go through significant first pass metabolism, so that administering K201 orally results in significant plasma levels of the M-II metabolite. Accordingly, some embodiments disclosed herein relate to the administration of K201 , e.g., in an oral dosage form, to achieve a combined plasma concentration K.201 and its metabolite(s), e.g., M-II, that is therapeutically effective. The accompanying data demonstrate that it is possible to achieve desired therapeutic effects, i.e., treatment and/or prevention of cardiac conditions such as cardiac rhythm disorders, by designing a therapy regimen, e g , involving administering K.201 in an oral dosage form, to provide a plasma concentration of K201 and M-II effective to treat or prevent the cardiac condition.
[0056] In some embodiments, the subject is administered K201, or a composition or formulation consisting of, consisting essentially of, or comprising K201 in multiple doses. For example, in some embodiments, the subject is administered K201 over a mutli-day period (e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, or more), according to a dosing schedule, wherein the dosing schedule requires no more than one, two, three, four, five, or six temporally-spaced doses per days. Preferably, the dosing schedule requires no more than two doses per day.
[0057] In some embodiments, the elimination half life is used to determine the dosage intervals of K201. For example, following administration of K201, or a formulation comprising, consisting essentially of, or consisting of K201, a peak blood concentration of K201 (Cmax) is reached at a first time, Tl . Subsequently, the plasma concentration of K201 decreases, until it reaches a minimum effective concentration (Cmec), at a second time, T2. In some embodiments, K201 or formulation comprising, consisting essentially of, or consisting of K201 is administered in multiple temporally-spaced dosages, according to a dosing schedule, wherein the time interval or spacing between doses is an interval, T3, greater than T2. For example, in some embodiments, T3 is selected such that the subject has a plasma level of K201 M-II at T3, such that either the level of M-II, or the combined plasma concentration of M-II and K201 at T3 are effective to treat or prevent a cardiac condition, such as arrhythmia. In some embodiments, the Cmax following administration is about 50 nM, 60 nM, 7OnM, 8OnM, 90 nM, 10OnM, 1 10 nM, 120 nM, 130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 210 nM, 220 nM, 230 nM, 240 nM, 250 nM, 260 nM, 270 nM, 280 nM, 290 nM, 300 nM, 310 nM, 320 nM, 330 nM, 340 nM, 350 nM, 360 nM, 370 nM, 380 nM, 390 nM, 400 nM, 410 nM, 420 nM, 430 nM, 440 nM, 450 nM, 460 nM, 470 nM, 480 nM, 490 nM, 500 nM, 510 nM, 520 nM, 530 nM, 540 nM, 550 nM, 560 nM, 570 nM, 580 nM, 590 nM, 600 nM, 610 nM, 620 nM, 630 nM, 640 nM, 650 nM, 660 nM, 670 nM, 680 nM, 690 nM, 700 nM, 710 nM, 720 nM, 730 nM, 740 nM, 750 nM, 760 nM, 770 nM, 780 nM, 790 nM, 800 nM, 810 nM, 820 nM, 830 nM, 840 nM, 850 nM, 860 nM, 870 nM, 880 nM, 900 nM, 910 nM, 920 nM, 930 nM, 940 nM, 950 nM, 960 nM, 970 nM, 980 nM, 990 nM, 1 μM, 10 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70μM, 80μM, 90 μM, lOOμM, 1 10 μM, 120 μM, 130 μM, 140 μM, 150 μM, 160 μM, 170 μM, 180 μM, 190 μM, 200 μM, 210 μM, 220 μM, 230 μM, 240 μM, 250 μM, 260 μM, 270 μM, 280 μM, 290 μM, 300 μM, 310 μM, 320 μM, 330 μM, 340 μM, 350 μM, 360 μM, 370 μM, 380 μM, 390 μM, 400 μM, 410 μM, 420 μM, 430 μM, 440 μM, 450 μM, 460 μM, 470 μM, 480 μM, 490 μM, 500 μM, 510 μM, 520 μM, 530 μM, 540 μM, 550 μM, 560 μM, 570 μM, 580 μM, 590 μM, 600 μM, 610 μM, 620 μM, 630 μM, 640 μM, 650 μM, 660 μM, 670 μM, 680 μM, 690 μM, 700 μM, 710 μM, 720 μM, 730 μM, 740 μM, 750 μM, 760 μM, 770 μM, 780 μM, 790 μM, 800 μM, 810 μM, 820 μM, 830 μM, 840 μM, 850 μM, 860 μM, 870 μM, 880 μM, 900 μM, 910 μM, 920 μM, 930 μM, 940 μM, 950 μM, 960 μM, 970 μM, 980 μM, 990 μM 1 mM, or less or more, or any number in between. In some embodiments, the Cmec of K201 and/or M-II is about 50 nM, 60 nM, 7OnM, 8OnM, 90 nM, 10OnM, 1 10 nM, 120 nM, 130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 210 nM, 220 nM, 230 nM, 240 nM, 250 nM, 260 nM, 270 nM, 280 nM, 290 nM, 300 nM, 310 nM, 320 nM, 330 nM, 340 nM, 350 nM, 360 nM, 370 nM, 380 nM, 390 nM, 400 nM, 410 nM, 420 nM, 430 nM, 440 nM, 450 nM, 460 nM, 470 nM, 480 nM, 490 nM, 500 nM, 510 nM, 520 nM, 530 nM, 540 nM, 550 nM, 560 nM, 570 nM, 580 nM, 590 nM, 600 nM, 610 nM, 620 nM, 630 nM, 640 nM, 650 nM, 660 nM, 670 nM, 680 nM, 690 nM, 700 nM, 710 nM, 720 nM, 730 nM, 740 nM, 750 nM, 760 nM, 770 nM, 780 nM, 790 nM, 800 nM, 810 nM, 820 nM, 830 nM, 840 nM, 850 nM, 860 nM, 870 nM, 880 nM, 900 nM, 910 nM, 920 nM, 930 nM, 940 nM, 950 nM, 960 nM, 970 nM, 980 nM, 990 nM, 1 μM, 10 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70μM, 80μM, 90 μM, lOOμM, 1 10 μM, 120 μM, 130 μM, 140 μM, 150 μM, 160 μM, 170 μM, 180 μM, 190 μM, 200 μM, 210 μM, 220 μM, 230 μM, 240 μM, 250 μM, 260 μM, 270 μM, 280 μM, 290 μM, 300 μM, 310 μM, 320 μM, 330 μM, 340 μM, 350 μM, 360 μM, 370 μM, 380 μM, 390 μM, 400 μM, 410 μM, 420 μM, 430 μM, 440 μM, 450 μM, 460 μM, 470 μM, 480 μM, 490 μM, 500 μM, 510 μM, 520 μM, 530 μM, 540 μM, 550 μM, 560 μM, 570 μM, 580 μM, 590 μM, 600 μM, 610 μM, 620 μM, 630 μM, 640 μM, 650 μM, 660 μM, 670 μM, 680 μM, 690 μM, 700 μM, 710 μM, 720 μM, 730 μM, 740 μM, 750 μM, 760 μM, 770 μM, 780 μM, 790 μM, 800 μM, 810 μM, 820 μM, 830 μM, 840 μM, 850 μM, 860 μM, 870 μM, 880 μM, 900 μM, 910 μM, 920 μM, 930 μM, 940 μM, 950 μM, 960 μM, 970 μM, 980 μM, 990 μM, 1 mM, or less or more, or any number in between, or less or more, or any number in between.
[0058] In accordance with the methods disclosed herein, in some embodiments, Tl is reached within 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 15 min, 20 min, 30 min, 40 min 50 min, 60 min, 70 min, 80 min, 90 min, 100 min, 1 10 min, 120 min, or longer, depending on the rate and route of administration. In some embodiments, T2 is reached within 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 15 min, 20 min, 30 min, 40 min 50 min, 60 min, 70 min, 80 min, 90 min, 100 min, 1 10 min, 120 min, 130 min, 140 min, 150 min, 160 min, 170 min, 180 min, 190 min, 200 min, 210 min, 220 min, 230 min, 240 min, 250 min, 260 min, 270 min, 280 min, 290 min, 300 min, 400 min, 410 min, 420 min, 430 min, 440 min, 450 min, 460 min, 470 min, 480 min, 490 min, 500 min, 510 min, 520 min, 530 min, 540 min, 550 min, 560 min, 570 min, 580 min, 590 min, 600 min, or less, or more, or any number in between. [0059] In some embodiments, the methods include the design of a course of therapy for at least a predetermined time period, wherein the course of therapy includes the administration of multiple doses of K201. In some embodiments, the time period is equal or greater than the time period to go from peak to trough plasma concentration levels of the M-II metabolite of K201. In some embodiments, the time period is equal or great than the half life of K201 , but less than the time period to go from peak to trough plasma concentration levels of M-II. Accordingly, the exemplary therapeutically effective amounts of K201 described herein, can, in some embodiments be administered on an hourly basis, e.g., every one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three hours, or any interval in between, or on a daily basis, every two days, every three days, every four days, every five days, every six days, every week, every eight days, every nine days, every ten days, every two weeks, every month, or more or less frequently, as needed to achieve the desired therapeutic effect. Preferably, K201 is administered at least every 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, every 24 hours, or any interval in between, or longer. In some embodiments, the K201 is provided in an oral dosage form.
[0060] In some embodiments, K201 can be provided in a single dose during the administration. For example, in some embodiments the subject is provided a single oral dose of K201. In some embodiments, about 2 mg/kg to 6 mg/kg or more of K201 can be provided in a single dose, for example in a continuous intravenous infusion. In other embodiments, K.201 can provided in more than one dose during the administration, for example, two, three or more doses of K201, can be provided in a single continuous intravenous infusion. Preferably, K201 is administered in multiple doses (i.e., more than one dose) in the methods described herein. Most preferably, the time period between sequential doses of K201 exceeds the half life of K201 , or T2 as discussed above. For example, in some embodiments, the time period between sequential doses of K201 greater than or equal to the elimination half time of K201.
[0061] In some embodiments K201 can be provided in a continuous infusion for a period of time of about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 1 1 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, or more. Preferably, K201 can be provided in a continuous infusion for a period of time of about 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours, 5.5 hours, 6 hours, or 6.5 hours, or any amount of time in between. In some embodiments, two doses of K201 can be provided in a continuous infusion over a period of about 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, or 7 hours. Optionally, the first dose can be provided over about 1.5 to about 2.5 hours, preferably 2 hours, and the second dose can be provided over about 3.5 hours, 4 hours, or 4.5 hours, preferably about 4 hours. In some embodiments, K201 is provided in a 1 minute infusion, a 2 minute infusion, a 3 minute infusion, a 4 minute infusion, a 5 minute infusion, a 6 minute infusion, a 7 minute infusion, an 8 minute infusion, a 9 minute infusion, a 10 minute infusion, an 1 1 minute infusion, a 12 minute infusion, a 13 minute infusion, a 14 minute infusion, a 15 minute infusion, a 16 minute infusion, a 17 minute infusion, an 18 minute infusion, a 19 minute infusion, a 20 minute infusion, a 21 minute infusion, a 22 minute infusion, a 23 minute infusion, a 24 minute infusion, a 25 minute infusion, a 26 minute infusion, a 27 minute infusion, a 28 minute infusion, a 29 minute infusion, a 30 minute infusion, or longer infusion, or any length of time in between, as described herein.
[0062] In some embodiments, the methods include the administration of a therapeutically effective amount of a composition comprising K201 or a pharmaceutically acceptable salt, ester, or amide thereof to the subject, and informing the subject or a medical care worker that administration of the composition can provide antiarrhythmic effects for a period of time following administration, wherein the time period exceeds the half life of K201. As used herein, the term "informing" means referring to or providing published material, for example, providing an active agent with published material to a user; or presenting information orally, for example, by presentation at a seminar, conference, or other educational presentation, by conversation between a pharmaceutical sales representative and a medical care worker, or by conversation between a medical care worker and a patient; or demonstrating the intended information to a user for the purpose of comprehension. [0063] A "medical care worker" means a worker in the health care field who may need or utilize information regarding an active agent, including a dosage form thereof, including information on safety, efficacy, dosing, administration, or pharmacokinetics. Examples of medical workers include physicians, pharmacists, physician's assistants, nurses, aides, caretakers (which can include family members or guardians), emergency medical workers, and veterinarians.
[0064] Accordingly, in some embodiments, the methods involve informing the subject and/or medical care working that administration of the K201 compositions can provide antiarrhythmic effects for a period of time exceeding about 2 hours, 3 hours, four hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 1 1 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days 5 days, 6 days, a week, or more.
[0065] In some embodiments, the methods include the step of designating a course of therapy that is intended to achieve treatment of a cardiac disorder, or maintenance of cardiac function (e.g., maintenance of normal sinus rhythm or the like), for at least a predetermined period, wherein the course of therapy includes administration of an a composition comprising K201, or pharmaceutically acceptable salt, ester, or amide thereof. In some embodiments, the K201 administration can be completed at least about 2 hours, 3 hours, four hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 1 1 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days 5 days, 6 days, a week, or more, or more prior to completion of the predetermined period for the course of the therapy.
[0066] In some embodiments, the additional therapeutic agent(s) and K201 or a pharmaceutically acceptable salt, ester, or amide thereof can be administered nearly simultaneously. These embodiments include those in which K201 and the other therapeutic agent(s) are in the same administrable composition, i.e., a single tablet, pill, or capsule, or a single solution for intravenous injection, or a single drinkable solution, or a single dragee formulation or patch, contains both compounds. The embodiments also include those in which each compound(s) is in a separate administrable composition, but the subject is directed to take the separate compositions nearly simultaneously, i.e., one pill is taken right after the other or that one injection of one compound is made right after the injection of another compound, etc.
[0067] In some embodiments, the levels of M-II and/or K201 in a subject (e.g., in the serum, in the urine, etc.) can be measured following administration of K201. The measurement of K201 and/or M-II can be preformed using routine diagnostic methods such as HPLC or bioassays.
[0068] In some embodiments, the methods described herein can include the step of measuring the presence or existence of symptoms or signs associated with the cardiac disorder, following administration of K201, or pharmaceutical composition comprising K201 to the subject. In some embodiments, the administration of K201 or a pharmaceutically acceptable salt, ester or amide thereof transforms the mammal, such that the cardiac condition is lessened, treated or prevented in the mammal. For example, in some embodiments, the administration of K201 , or pharmaceutical composition comprising K201 , causes a cessation or an amelioration of a cardiac rhythm disorder in a subject with an existing cardiac rhythm disorder, or, preserves regular sinus rhythm.
[0069] In some embodiments, the subject is administered a composition that comprises, consists essentially of, or consists of, K201 or a pharmaceutically acceptable salt, ester, or amide thereof. The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to a subject to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutical salts can also be obtained by reacting a compound disclosed herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxyrnethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like. Other exemplary salts include salts derived from organic acids, such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like; and salts derived from ammo acids, such as glutamic acid or aspartic acid.
[0070] The term "ester" refers to a chemical moiety with formula -(R)n-COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
[0071] An "amide" is a chemical moiety with formula -(R)n-C(O)NHR' or -(R)n-NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1. An amide may be an amino acid or a peptide molecule attached to a compound of the embodiments disclosed herein, e.g., a K201 metabolite such as, for example M-IL.
[0072] Any amine, hydroxy, or carboxyl side chain on the compounds disclosed herein, or esters, or amides of the compounds disclosed herein can be esterified or amidified. The procedures and specific groups to be used to achieve this end is known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.
[0073] As used herein, "administering" is intended to encompass administration of a drug to a subject or patient, including administration by a third party and self- administration.
[0074] In the embodiments described herein, K201 can be provided in a pharmaceutical composition that comprises, consists essentially of, or consists of K201 and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof. The term "pharmaceutical composition" refers to a mixture of a compound of the invention with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
[0075] The term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.
[0076] The term "diluent" defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
[0077] The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
[0078] The pharmaceutical compositions described herein can be administered to a human subject per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.
[0079] Alternatively, one can administer the compounds disclosed herein in a local rather than systemic manner, for example, via injection of the compound directly in the cardiac area, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.
[0080] Pharmaceutical compositions for use in accordance with the embodiments described herein thus can be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well- known techniques, carriers, and excipients can be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
[0081] For injection, the agents of the invention may be formulated in aqueous solutions or lipid emulsions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
[0082] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination of the invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethy lcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
[0083] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [0084] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Furthermore, the formulations of the present invention may be coated with enteric polymers. All formulations for oral administration should be in dosages suitable for such administration.
[0085] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
[0086] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[0087] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
[0088] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[0089] A non-limiting example of a formulation of K201 for parenteral delivery is as follows:
Figure imgf000031_0001
[0090] The skilled artisan will readily appreciate, however, that any of the non- active ingredients of the formulation shown above can be substituted with art-accepted equivalents.
[0091] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0092] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
[0093] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0094] A pharmaceutical carrier for the compounds described herein is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant POLYSORBATE 80™, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80 ; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
[0095] Alternatively, other delivery systems for pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
[0096] Many of the compounds used in the pharmaceutical combinations described herein can be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acid or base forms.
[0097] The compositions may, if desired be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
EXAMPLES
[0098] Having now generally described the invention, the same will become better understood by reference to certain specific examples which are included herein for purposes of illustration only and are not intended to be limiting unless other wise specified. All referenced publications and patents are incorporated, in their entirety by reference herein.
EXAMPLE 1 Preparation of M-II Free Base
[0099] The M-II metabolite of K201 was prepared as follows as depicted in Scheme I5 below:
Scheme
Figure imgf000034_0001
[0100] In step (a), 5-methoxy-2nitrobenzoic acid (SIGMA Aldrich, Cat. No. 391999, St. Louis, MO), was treated with a reducing agent, in the presence of a catalyst, H2, Pd/C, MeOH, at room temperature, as described in U.S. Patent Application Publication No. 2004/0229871. In step (b), the compound formed in step (a) was treated with a diazotizing agent and a disulfide, NaNO2, HC1/H2, Na2S2. The compound formed in step (b) was treated with a SOCl2 followed by H2NCH3CH2Cl, H2NCH2Cl. The compound formed in step (c) was reduced/cyclized by treating the compound with sodium borohydride in ethanol, as described in J. Heterocyl. Chem (1988), 25:1007 or Eur. J. Med. Chem. Chim. Ther. (1993) 28(3):213. The compound formed in step (d) was treated with BH3 or the like, to form an amine. The compound formed in step (e) was treated with acryloyl chloride toluene in the presence of Na2Co3. The compound formed in step (f) was oxidized with meta- chloroperbenzoic acid in dichloromethane at a low temperature. Finally, the compound formed in step (g) was converted to M-II by treating with 4-benzylpiperidine as described in J. Am. Chem. Soc. (1957) 79:3805. EXAMPLE 2 Pharmacokinetic Properties of K201
[0101] To determine the pharmacokinetic properties of K201 , 31 healthy volunteers (human) were divided into treatment groups, as indicated in Table 2, below.
[0102] K.201 , in the indicated amounts, was administered to the subjects via intravenous injection over 10 minutes. At 0, 3, 5, 10, 15, 30, 45 min and 1 , 2, 3, 4, 6, 8, 12, 24 hours, a blood sample was obtained from the subject and the plasma was analyzed via HPLC to determine the concentration of K201. Urine samples were obtained from subjects at 0, 2, 4, 8, 12 and 24 hours, and analyzed via HPLC for K201. The data are presented in Table 2, below.
[0103] K201 exhibited biphasic elimination after intravenous injection, with rapid distribution (alpha phase) followed by a slower elimination (beta phase). The peak plasma K201 concentrations and the AUC(O.X) values appeared to increase in proportion to increasing dose from 10 to 500 μg/kg (Table 4). In all dose groups, drug distribution was rapid, with an average initial (alpha) half-life of 2 to 3 minutes, and mean terminal elimination half-life of about 2 hours. Volume of distribution (Vss) and clearance (CL) appeared to be independent of dose, with Vss averaging about 1.3 L/kg and CL averaging approximately 0.5 L/h/kg. Urinary excretion of K201 was very low, averaging 0.2% of the administered dose in all dose groups.
TABLE 4 PHARMACOKINETIC PARAMETERS FOLLOWING A SINGLE 10-MINUTE
K201 IV INFUSION: MEAN ± SD)
Dose Group (μg/kg)
Parameter 10 • 30 60 100 200 400 500
N 3 3 5 6 5 6
Cmax 18.5 ± 7.7 60.7 ± 23.9 139 ± 46 260 ± 74 445 ± 138 902 ± 323 1 127 ± 239 (ng/mL)
Xυ2x (min) 2.9 ± 0.9 2.6 ± 1.4 2.0 ± 0.8 2.0 ± 0.5 2.3 ± 0.5 2.3 ± 0.8 2.2 ± 0.5 tl/2β (h) 2.4 ± 0.2 2.3 ± 0.2 2.3 ± 0.2 2.0 ± 0.3 2.3 ± 0.4 2.2 ± 0.3 2.3 ± 0.3
AUC(O-K) 19.2 ± 2.2 58.9 > ± 3.4 125 ± 5 239 ± 15 435 : 52 890 ± 1 12 1061 ± 97 (ng h/mL)
CL (L/h/kg) 0.53 ± 0.06 0.51 ± 0.03 0.48 ± 0.02 0.42 ± 0.03 0.47 ± 0.05 0.45 ± 0.05 0.48 ± 0.05
Vss (L/kg) 1.6 ± 0.3 1.5 ± 0.2 1.3 ± 0.1 1.1 ± 0.2 1.3 ± 0.3 1.2 ± 0.2 1.3 ± 0.2
Ae(o-24) ND ND 0.15 ± 0.18 0.06 ± 0.07* 0.12 ± 0.19 0.01 : D.02* 0.10 ± 0.05 (% of dose)
' n=6 ND = not detected Ae = cumulative urinary excretion EXAMPLE 3
Pharmacokinetic Properties of M-II
[0104] To determine the pharmacokinetic properties of the K201 metabolite M-II, oral K201 was encapsulated in gelatin capsules. Forty-one 41 healthy volunteers (human) were divided into treatment groups, as indicated in Table 5, below.
[0105] K201 was administered via the oral route in the indicated amounts. At 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 h post-dose, a blood sample was obtained from the subject and plasma was analyzed via HPLC to determine the concentration of M-II. The data are presented in Table 5, below.
TABLE 5
Figure imgf000037_0001
ϊ
EXAMPLE 4
[0106] In a study conducted to measure the in vitro effect of K201 metabolites, mammalian cells were stably transfected with the cloned human genes encoding the cardiac ion channels listed in Table 6.
[0107] Stock solutions of K201, K201 M-II and control solutions were prepared in dimethyl sulfoxide (DMSO) and stored frozen. Fresh dilutions of the stock were made in HEPES buffered saline, such that final test formulations did not exceed a DMSO concentration of >0.3%. For each ion channel tested, a positive control was prepared. The identity of the positive controls is listed in Table 6.
[0108] Table 6 lists the cardiac ion channels tested:
TABLE 6
Figure imgf000038_0001
[0109] A glass-lined 96 well compound plate was loaded with the appropriate amounts of test and control solutions and placed in the well of a PATCHXPRESS® ion channel reader (Model 7000A, Molecular Devices, Union City, CA). Cell Culture Procedures:
[0110] HEK293 cells were stably transfected with the appropriate ion channel cDNA encoding the pore-forming channel subunit. Stable transfectants were selected using the G418-resistance gene incorporated into the expression plasmid. Selection pressure was maintained with G418 in the culture medium. Cells were cultured in D-MEM/F-12 (Dulbecco's Modified Eagle Medium/Nutrient Mixture F- 12) supplemented with 10% FBS, 100 U/mL penicillin G sodium, 100 μg/mL streptomycin sulfate and 500 μg/mL G418.
[0111] CHO cells were stably transfected with the appropriate ion channel cDNAs. Cells were cultured in Ham's F-12 supplemented with 10% FBS, 100 U/mL penicillin G sodium, 100 μg/mL streptomycin sulfate, and the appropriate selection antibiotics. Before testing, cells in culture dishes were washed twice with Hank's Balanced Salt Solution, treated with trypsin, and re-suspended in the culture media (4-6 x 106 cells in 20 mL). Cells in suspension were allowed to recover for 10 minutes in a tissue culture incubator set at 370C in a humidified 95% air/5% CO2 atmosphere. Test Methods
[0112] All experiments were performed at room temperature.
[0113] Four concentrations, i.e., 0.1, 1, 10 and 100 μM, of K201 Mil were applied at 5 minute intervals to naϊve cells (n > 2), where n= the number cells/concentrations; up to 2 concentrations/cell). Solution exchanges were performed in quadruplicate, and consisted of aspiration and replacement of 45 μL of the total 50 μL volume of the extracellular well of the SEALCHIP™ planar voltage clamp tool. Duration of exposure to each test article concentration was 5 min.
TABLE 7
Figure imgf000039_0001
[0114] For the positive control treatment groups, vehicle was applied to naϊve cells (n > 2, where n= the number cells), for a 5-10 minute exposure interval. Each solution exchange, performed in quadruplicate, consisted of aspiration and replacement of 45 μL of the total 50 μL volume of the extracellular well of the SEALCHIP™ planar voltage clamp tool. After vehicle application, the positive control was applied in the same manner, to verify sensitivity to ion channel blockade.
[0115] Intracellular solution (Table 8) was loaded into the intracellular compartments of the SEALCHIP™ planar voltage clamp tool. Cell suspension was pipetted into the extracellular compartments of the SEALCHIP™ planar voltage clamp tool. After establishment of a whole-cell configuration, membrane currents were recorded using dual- channel patch clamp amplifiers in the PATCHXPRESS® ion channel reader. Before digitization, the records were low-pass filtered at one-fifth of the sampling frequency. Valid whole-cell recordings met the following criteria: 1) Membrane Resistance (Rm) > 200 MΩ; and 2) Leak current < 25% channel current. hERG Test Procedure
[0116] Onset and block of hERG current was measured using a stimulus voltage pattern consisting of a 500 ms prepulse to -4OmV (leakage subtraction), a 2-second activating pulse to +40 mV, followed by a 2-second test pulse to -40 mV. The pulse patter was repeated continuously at 10 second intervals, from a holding potential of -80 mV. Peak tail current was measured during the -40 mV test pulse. Leakage current was calculated from the current amplified evoked by the prepulse and subtracted from the total membrane current record. hNayl .5 Test Procedure
[0117] Onset and steady-state block of hNavl.5 current was measured using a double pulse pattern consisting of a hyperpolarizing conditioning pulse (-10OmV amplitude, 200 ms duration) followed immediately by a depolarizing test pulse depolarization (-15 mV amplitude, 10 ms duration), form a holding potential of -80 mV. The pulse pattern was repeated at 10 second intervals. Peak and test pulse current amplitudes were measured. hCayl .2 Test Procedure [0118] Onset and steady state block of hCavl .3/β2 channels was measured using a stimulus voltage pattern consisting of a depolarizing test pulse (duration, 200 ms; amplitude, 10 mV) at 10 second intervals from a -80 mV holding potential. Test article concentrations were applied cumulatively in ascending order without washout between applications. Peak current was measured during the step to 10 mV. 10 μM of nifedipine was added at the end of each experiment to block hCavl .2 current. Leak current was digitally subtracted from the total membrane current record. hKvLQTl/hminK Test Procedure
[0119] Onset and steady state block of hKvLQTl/hminK current was measured using a pulse pattern with fixed amplitudes (depolarization; +40 mV for 2 seconds; repolarization: -40 mV for 0.5 seconds) repeated at 15 second intervals from a holding potential of -80 mV. Current amplitude was measured at the end of the step to +40 mV. 300 μM of Chromanol 293B was added at the end of each experiment to block hKvLQTl/hminK current. Leakage current was measured after chromanol 293B addition, and subtracted from the total membrane current record. hKv4.3 Test Procedure
[0120] Onset and steady state block of hKv4.3 current were measured using a pulse pattern with fixed amplitudes (depolarization: 0 mV for 300 ms,), repeated at 10 second intervals from a holding potential of -80 mV. Peak and sustained test pulse current amplitudes were measured during the step to zero mV. hKyl .5 Test Procedure
[0121] Onset and steady state block of hKvl .5 current was measuring using a pulse pattern with fixed amplitudes (depolarization: +20 mV amplitude, for 300 ms) repeated at 10 second intervals from a holding potential of -80 mV.. Current amplitude was measured at the end of the step to +20 mV. hCav3.2 Test Procedure
[0122] Onset and steady state block of hCav3.2 current was measured using a double pulse pattern consisting of a hyperpolarizing conditioning pulse (-120 mV amplitude, 250 ms duration) followed immediately by a depolarizing test pulse depolarization (-30 mV amplitude, 50 ms duration) from a -80 mV holding potential. The pulse pattern was repeated at 10 second intervals and peak test current amplitudes were measured. hKir2.1 Test Procedure
[0123] Onset and steady state block of hKir2.1 current was measuring using a pulse pattern with fixed amplitudes (hyperpolarization: -1 10 mV amplitude, for 300 ms) repeated at 10 second intervals from a holding potential of -70 mV. Current amplitude was measured at the end of the step to -110 mV. hKir3. l/hKir3.4 Test Procedure
[0124] Onset and steady state block of hKir3.1/hKir3.4 current was measuring using a pulse pattern with fixed amplitudes (hyperpolarization: -100 mV amplitude, for 400 ms), followed by a 1 -second ramp from -100 mV to +40 mV) repeated at 10 second intervals from a holding potential of -70 mV.. Current amplitude was measured at the end of the step to -100 m V. hHCN2 Test Procedure
[0125] Onset and steady state block of hHCN2 current was measuring using a pulse pattern with fixed amplitudes (hyperpolarization: -120 mV amplitude, for 1 second) repeated at 10 second intervals from a holding potential of -30 mV. Current amplitude was measured at the end of the step to -120 mV. hHCN4 Test Procedure
[0126] Onset and steady state block of hHCN4current was measuring using a pulse pattern with fixed amplitudes (hyperpolarization: -120 mV amplitude, for 1 second) repeated at 10 second intervals from a holding potential of -30 mV. Current amplitude was measured at the end of the step to -120 mV.
[0127] hKir6.2/SUR2A Test Procedure
[0128] The hKir6.2/hSUR2A current was activated with a 5 minute application of 100 μM pinacidil. Onset and steady state block of the current was measured using a pulse patter with fixed amplitudes (hyperpolarization: -1 10 mV amplitude, for 400 ms), followed by a 1 -second ramp from -100 mV to +10 mV) repeated at 10 second intervals from a holding potential of -60 mV.. Current amplitude was measured at the end of the step to +10 mV. TABLE 8
h
Figure imgf000043_0001
Data Analysis
[0129] Data was analyzed using conventional software. Steady sate is defined by the limiting constant rate of change with time (linear time dependence). The steady state before and after teat article application was used to calculate the percentage of current inhibited at each concentration. Concentration-response date was fit to an equation of the following form:
% Bock = { l-l/[l+([Test]/IC50)N]} * 100
[0130] where [Test] is the concentration of M-II, IC50 is the concentration of M-II producing half-maximal inhibition, N is the Hill coefficient, and % Block is the percentage of ion channel current inhibited at each concentration of the test article. Nonlinear test squares fits will be solved with the Solver add-in for Excel 2000 Microsoft, Redmond, WA). If the test article produced greater than 50% block at the highest concentration, IC50 was established.
[0131] The effect of K201 M-II on cardiac ion channels (expressed in the mammalian cell lines indicated above) was evaluated at room temperature using the PatchXpress™ 7000A parallel patch clamp system (Molecular Devices, Sunnyvale, CA). The K201 metabolite M-II was evaluated at 0.1, 1, 10 and 100 μM, with each concentration tested on 2-3 cells (n > 2). The duration of exposure to each test article concentration was 5 minutes.
[0132] Under the experimental conditions the K201 metabolite M-II blocked lκr (hERG) channels in a concentration dependent fashion yielding an IC50 value of 1.328 μM. (Table 2, Figure 1).
[0133] Under the experimental conditions the K201 metabolite M-II blocked Iκr (hERG) channels in a concentration dependent fashion yielding an IC50 value of 0.372 μM. (Table 9, Figure 1). TABLE 9
Figure imgf000045_0001
[0134] Under the experimental conditions the K201 metabolite M-II free base blocked IN8 (hNal.5) sodium channels in a concentration dependent fashion yielding an IC50 value of 8.333 μM. (Table 10 Figure 2).
TABLE 10
Figure imgf000045_0002
[0135] Under the experimental conditions the K201 metabolite M-II blocked Iκs (hKvLQTl/hminK) potassium channels in a concentration dependent fashion yielding an IC50 value of > 100 μM. (Table 11). TABLE 1 1
Figure imgf000046_0001
[0136] Under the experimental conditions the K201 metabolite M-II blocked It0 (hKv4.3) potassium channels in a concentration dependent fashion yielding an IC50 value of 50.225 μM. (Table 12).
TABLE 12
Figure imgf000046_0002
[0137] Under the experimental conditions the K201 metabolite M-II blocked IκUr (hKvl .5) potassium channels in a concentration dependent fashion yielding an IC50 value of 4.994 μM. (Table 13, Figure 3).
TABLE 13
Figure imgf000046_0003
Figure imgf000047_0001
[0138] Under the experimental conditions the K201 metabolite M-II blocked Ica,L (hCavl .2) calcium channels in a concentration dependent fashion yielding an IC50 value of 1.129 μM. (Table 14, Figure 4).
TABLE 14
Figure imgf000047_0002
[0139] Under the experimental conditions the K201 metabolite M-II blocked Ica,τ (hCav3.2) calcium channels in a concentration dependent fashion yielding an IC50 value of 49.172 μM. (Table 15, Figure 5).
TABLE 15
Figure imgf000047_0003
[0140] Under the experimental conditions the K201 metabolite M-II blocked Iκi(hKir2.1) potassium channels in a concentration dependent fashion yielding an IC50 value of≥lOO μM. (Table 16).
TABLE 16
Figure imgf000048_0001
[0141] Under the experimental conditions the K201 metabolite M-II blocked If (hHCN2) potassium channels in a concentration dependent fashion yielding an IC50 value of >100 μM. (Table 17).
TABLE 17
Figure imgf000048_0002
[0142] Under the experimental conditions the K201 metabolite M-II blocked If (hHCN4) potassium channels in a concentration dependent fashion yielding an IC50 value of >100 μM. (Table 18). TABLE 18
Figure imgf000049_0001
[0143] Under the experimental conditions the K201 metabolite M-II blocked IAch (hKir3.1/hKir3.4) potassium channels in a concentration dependent fashion yielding an IC50 value of 40.524 μM. (Table 19, Figure 6).
TABLE 19
Figure imgf000049_0002
[0144] Under the experimental conditions the K201 metabolite M-II blocked IKATP (hKir6.2/SUR2A) potassium channels in a concentration dependent fashion yielding an IC50 value of 6.820 μM. (Table 20, Figure 7). TABLE 20
Figure imgf000050_0001
[0145] The data above demonstrate that K201 metabolites possess properties that render them useful in the treatment and/or prevention of cardiac disorders, such as cardiac rhythm disorders, e.g., atrial cardiac rhythm disorders or ventricular cardiac rhythm disorders, including atrial flutter, other supraventricular tachycardias, ventricular tachycardia (e.g., Torsade des Pointes, catecholaminergic polymorphic ventricular tachycardia, and monomorphic ventricular tachycardia), as well as disorders such as sudden cardiac death, acute and/or chronic heart failure, (e.g., left ventricular systolic dysfunction or left ventricular diastolic dysfunction), acute coronary syndrome, such as myocardial infarction, angina, acute and/or chronic hypertension, (e.g., catecholamine-induced hypertension), pulmonary edema, chronic obstructive pulmonary disease and the like.
[0146] The following example describes in vivo studies to determine the efficacy of M-II as a therapeutic for treating or preventing atrial fibrillation.
EXAMPLE 5 M-II Effects on Atrial Effective Refractory Period in vivo
[0147] The anesthetized dog model is a standard model for cardiovascular pharmacology investigations. Accordingly, anesthetized mongrel dogs were used, as described below, to determine the dose dependent increase in atrial effective refractory period (AERP) of K201 metabolite M-II and corresponding plasma levels of M-II, and to determine the effects of M-II on the surface ECG at designated dose levels.
[0148] The test article dosing formulations were administered intravenously to anesthetized mongrel dogs as shown in Table 21. TABLE 21
Figure imgf000051_0001
[0149] ** Initial infusion of 0/3 mg/kg/min for 2 minutes, followed by 0.03 mg/kg/min for 30 minutes
[0150] ***Dose based on mg M-II free-base. Dosing formulation is 1.39 mg/mL M-II free base (2 mg/mL M-II citrate salt). Test System
[0151] Upon arrival, dogs were individually housed in pens equipped with an automatic watering system. A standard commercial dog chow (approximately 800 g, Hill's, Prescription Diet IiD) was made available to each dog once daily. Animals were fasted overnight prior to surgery.
[0152] Prior to each animal's treatment, the following surgical procedure was performed on each animal. All dogs were administered morphine (2 mg/kg subcutaneously) 19-22 minutes prior to induction of anesthesia. Dogs were anesthetized with a bolus of 2.5% a-chloralose at 120 mg/kg IV, followed by a constant infusion of a-chloralose at 33 mg/kg/hr IV, administered in the right or left femoral vein. One (1) animal (1003B) however, had its infusion reduced (57 minutes post initiation of the dosing) and stopped for 5 minutes (at 1 16 minutes post initiation of the dosing) due to low arterial blood pressure, and another animal (1001 A), had its infusion reduced to 25 mg/kg/hr (at 199 minutes post initiation of dosing) also due to low arterial blood pressure during the experiment.
[0153] Additional morphine injections of at a dose of 0.5 mg/kg per injection were administered subcutaneously approximately every 2 hrs to maintain the level of analgesia throughout the experiment. Dogs were placed on a heating pad set to maintain the animal's body temperature at approximately 37°C. Body temperature was monitored throughout the experiment via a rectal thermometer. Dogs were intubated and provided assisted ventilation supplemented with oxygen and medical air to maintain oxygenation within the normal physiologic range. The animals were mechanically ventilated using a rebreathing system at a rate 20 breaths/minute, a tidal volume of 13 mL/kg and an inspiratory pressure of 19-20 CmH2O. Lidocaine 2% was not used during intubation as the animals did not present signs of reflexes. The following parameters were regularly monitored in order to ensure proper ventilation of the animals but will not be reported: SpO2, inspiratory and expiratory CO2, inspiratory O2 and respiratory rate.
[0154] For each dog, a fluid filled catheter system with transducer was used to measure the arterial pressure from the femoral artery. A sternotomy was performed, and the pericardium opened from which a sling was created for the heart. With the heart exposed, epicardial bipolar pacing and recording electrodes were placed on the right and left cardiac atrial and ventricular appendages. In addition, an indwelling catheter was placed in the right femoral or saphenous vein for administration of Lactated Ringer's at 10 mL/kg/hr throughout the course of the anesthesia. In one (1) animal (1003B) out of three (3), this rate was increased to approximately 20 ml/kg/hr (500 ml/hr) for 13 minutes due to low arterial blood pressure.
[0155] Following surgical preparation and instrumentation, hemodynamic and electrocardiographic parameters were allowed to stabilize for at least 30 minutes. Preparation of Dosing Formulations
[0156] Each formulation was prepared by dissolving the appropriate amount of Sorbitol into 2/3 of the final volume of Sterile Water for Injection USP under continuous stirring for 5 minutes or until the solution was clear. The formulation's pH was adjusted under continuous stirring using a citric acid monohydrate (with an approximate ratio of 0.34 mg/mL of solution), to reach a pH in the range of 3.0 to 4.0. The appropriate amount of test article powder was then weighed (2 mg M-II citrate salt/mL) and added into the solution. The preparation was mixed until completely dissolved (using a magnetic stir plate) and the pH was recorded. Finally, the pH of the formulation was adjusted using a solution of O. IN NaOH, to reach a pH of 3.25±0.1. The preparation was then made up to the final volume with Sterile Water for Injection USP in order to reach the required concentration. The final pH was then recorded as 3.00 to 3.30.
[0157] The formulations were filtered through a 0.2211m Polyethersulphone (PES) filter into an amber glass vial, or a clear glass vial covered with aluminum foil. Administration of M-II [0158] Each dose was administered intravenously as an infusion consisting of an initial infusion of 0.3 mg/kg/min for 2 minutes followed by 0.03 mg/kg/min for 30 minutes via the left saphenous vein.
[0159] All dosings were undertaken as set forth above, with the exception that due to unknown reason, the initial infusion (0.3 mg/kg/min for 2 minute) for one dog terminated 27 seconds earlier while presenting a positive deviation of 1 1.83% above theoretical dose volume. One dog also presented a positive deviation of 14.37% above theoretical dose volume for the same infusion but terminated the infusion as indicated. The remaining dosings occurred without any notable deviations from theoretical doses. Surface Electrocardiography
[0160] Prior to treatment, electrocardiograms (limb leads I, II and III and leads a VR, a VL and a VF) were obtained from all animals and evaluated in order to ensure suitability for use on the study.
[0161] During the treatment period, ECG waveforms were monitored and recorded continuously using the Dataquest ART 3.01 Telemetry system via a transmitter (TL1OM3-D70-EEE) connected using external leads. Average values for lead II were calculated over 5 seconds due to pacing. The QT interval was corrected for heart rate changes using the Fredericia's and Van de Water's formulas. Computer analysis of ECG intervals (RR, PR, QRS, QT and QTc) was performed at approximately the following timepoints in all treatment groups: before infusion, continuously during infusion (approximately at 1 minute interval), at 10-minute intervals for the first 30 minutes post infusion, and at 20-minute intervals for the remainder of the study (total = 4 hours after completion of infusion).
[0162] Tracings were assessed for gross changes indicative of cardiac electrical abnormalities. Heart rate (lead II), rhythm or conduction abnormalities, QT and corrected QT (QTc) intervals were also evaluated. Tabular data of heart rates and QT and QTc intervals are presented for animals 1 through 3 in Tables 22-24, respectively. TABLE 22
Figure imgf000054_0001
TABLE 23
Figure imgf000055_0001
TABLE 24
Figure imgf000056_0001
Atrial Effective Refractory Period and Conduction Time Determinations
[0163] A programmable stimulator (Caltronics Inc.) connected to pacing cables was used for atrial pacing. Initially, the right and left atrial diastolic pacing threshold were determined at 2 msec pulse duration, by decrementing pulse amplitude (mA) gradually until consistent loss of atrial capture was observed. Subsequently, the pulse amplitude was increased to approximately twice this value. To determine atrial effective refractory period (AERP), pacing from right and left atrial epicardial bipolar electrodes was done sequentially at basic drive cycle lengths (S 1 S 1) of 360, 300, and 200 msec for eight (8) beats. Then, a premature atrial stimuli (S1S2) was introduced, decrementing by 5 msec after each drive cycle to determine AERP. AERP was defined as the longest S1S2 interval that did not produce atrial capture. Similar measurements were performed to determine the left-ventricular ERP at an SlSl of 300 ms. Also, inter-atrial conduction time was used to provide an estimate of atrial conduction velocity since the distance between electrodes was constant but unknown. Inter-atrial conduction time was determined once during each drive cycle (SlSl 360, 300 and 200 msec) by measuring the stimulus to contralateral local atrial electrocardiogram interval. All measurements were performed at baseline prior to infusion, 15 minutes into the infusion (for Group 1), immediately after completion of infusion, at 30 minutes, 1 hour, 2 hours and 4 hours after completion of infusion. ECG intervals were measured using a computerized system (Grasslab®, Astro-Med Inc.).
[0164] AERP and VERP measurements are shown in Figures 8A-8D and Figure 9. As shown, the K201 metabolite M-II increased atrial ERP with a slight reverse use-dependency. The significant effects lasted more than 2 and 4 hours in the left atrium (Figures 8A-8B) and right atrium (Figures 8C-8D), respectively. The K201 metabolite M-II did not affect left ventricular ERP (Figure 9). Conduction time measurements are depicted graphically in Figures 10A-10B. The K201 metabolite M-II did not affect intra-atrial conduction time. Blood pressure measurements are depicted graphically in Figures 1 IA-I IB. The K201 metabolite M-II caused a mild downward drift in blood pressure, suggesting that K201 has hypotensive tendencies. Sinus cycle length changes are depicted graphically in Figures 12A-12B. Sinus cycle length decreased consistently during the experiment. The time course of the changes were slower compared to atrial ERP changes and were progressive, rather than concentration-dependent. Pharmacokinetic Profiling
[0165] Venous blood samples (~1.3 mL/sample) were collected from the left jugular or left femoral at the following timepoints: [0166] o Pre-Rx
[0167] o Immediately post end Rx 1 (end of first infusion) [0168] o 15 min post start Rx 2 (i.e., during the second infusion) [0169] o immediately post end Rx 2 (i.e. at the end of infusion) [0170] o and at 30 minutes, 1 hour, 2 hours and 4 hours post end Rx 2 [0171] Blood samples were collected into tubes containing lithium heparin. Samples were centrifuged at 1500 g for a minimum of 10 minutes. The plasma was transferred into 2 aliquots containing at least 0.25 ttiL. Each plasma sample was placed on dry ice and then stored frozen (-7O0C ± 100C), pending shipment, on dry ice, to MicroConstants, San Diego, CA. Results
[0172] As expected for an IKr blocker, infusion of K201 metabolite M-II at 1500 μg/kgu(300 μg/kg/minute x 2 m inute followed by 30 μg/kg/minute x 30 minute), presented evidence of QTc prolongation ranging from + 1 1 to +25 msec immediately post initiation of the administration (1 min post-dosing start). QTc prolongation attained +25 to +37 msec during dosing and was relatively sustained throughout the monitoring period. However, beginning at 16 minutes post initiation until completion of dosing, variable changes in QTcV were observed which returned to elevated levels (+16 to +25 msec) by the end of the dosing period. Concurrently, heart rate presented variations that correlated with the QTcV changes.
[0173] Once the dosing was completed, a second series of changes occurred (beginning at 32 to 62 minutes post initiation of dosing) where a slight to severe decrease in QTcV was observed. In two animals out of three, this decrease brought the original QT prolongation to baseline levels, while for one animal out of three this decrease resulted in a QT shortening (-45 msec). These observations were correlated with moderate to severe increase in heart rate reaching +42% to + 109% from baseline values.
[0174] Significant PR interval changes were only observed in one animal out of three, and between 2 and 1 1 min post initiation of the test article administration. This period presented evidence of PR prolongation (+9 to + 16 msec) reaching + 12.5%, while heart rate presented variation which ranged between -0.6% to +4.7%. Part of this prolongation may be due to the decreased heart rate but a drug effect (e.g. calcium channel block) may also be involved.
Atrial Effective Refractory Period and Conduction Time Determinations
[0175] M-II produced clear atrial ERP increases that were important in both atria. The increases were substantial and had the time course expected for a direct drug action. These changes would be expected to translate into antiarrhythmic actions against reentrant atrial arrhythmias, especially AF. The drug had no discernible effects on ventricular ERP or interatrial conduction time.
[0176] Drug infusion was associated with small changes in blood pressure (slight decrease) and sinus rate (slight to moderate fastening). These actions would not be expected to impair antiarrhythmic properties or cause untoward side effects even if they are drug-related.
[0177] The electrophysiological results described herein demonstrate that M-II has atrial antiarrhythmic properties in vivo, confirming its usefulness as a therapeutic for treating and preventing cardiac rhythm disorders.
EXAMPLE 6 Treatment of Atrial Fibrillation in a Subject
[0178] A subject presents with atrial fibrillation to the hospital, physician's office or clinic. To treat the atrial fibrillation, the subject is administered 2 mg/kg to 6 mg/kg mg K201 via intravenous injection over 10 minutes. The subject's cardiac rhythm is monitored. The subject receives one or more sequential oral doses of K201 in order to maintain a steady state plasma concentration of M-II. The time between the sequential doses of K201 vary from 5 hours to 12 hours.
[0179] The atrial fibrillation subsides or ceases following administration of K201.
EXAMPLE 7 Treatment of Atrial Fibrillation in a Subject with Congestive Heart Failure
[0180] A subject with congestive heart failure present with atrial fibrillation to the hospital, physician's office or clinic. To treat the atrial fibrillation, the subject is administered 2 mg/kg to 6 mg/kg K201 via intravenous injection over 10 minutes. The subject's cardiac rhythm is monitored. The subject receives one or more sequential oral doses of K201 in order to maintain a steady state plasma concentration of M-II. The time between the sequential doses of K201 vary from 5 hours to 12 hours. [0181] The atrial fibrillation subsides or ceases following administration of K201.
EXAMPLE 8 Treatment of Torsade des Pointes in a Subject
[0182] A subject presents with Torsade des Pointes to the hospital, physician's office or clinic. To treat the Torsade des Pointes, the subject is administered 2 mg/kg to 6 mg/kg K201 via intravenous injection. The subject's sinus rhythm is monitored. The subject receives one or more sequential doses of K201 in order to maintain a steady state plasma concentration of M-II. The time between the sequential doses of K201 vary from 5 hours to 12 hours.
[0183] The Torsade des Pointes subsides or ceases following administration of K201.
EXAMPLE 9 Treatment of Heart Failure in a Subject
[0184] A subject presents with CHF arising from an acute injury to the heart, such as a myocardial infarction. The subject can exhibit abnormalities in the left ventricle, as evidenced by echocardiogram.
[0185] To treat the CHF, the subject is administered 2 mg/kg to 6 mg/kg K201 via intravenous injection. The subject's sinus rhythm and ejection fractions are monitored. The subject receives one or more sequential doses of K201 in order to maintain a steady state plasma concentration of M-II. The time between the sequential doses of K201 vary from 5 hours to 12 hours.
[0186] One or more of the symptoms of heart failure improves following administration of K201.
EXAMPLE 10
Treatment of Heart Failure in a Subject
[0187] A subject presents with diastolic heart failure. To treat the heart failure, the subject is administered 2 to 6 mg K201 via intravenous injection. The subject's sinus rhythm and ejection fractions are monitored. The subject receives one or more sequential doses of K201 in order to maintain a steady state plasma concentration of M-II. The time between the sequential doses of K201 vary from 5 hours to 12 hours.
[0188] One or more of the symptoms of diastolic heart failure improves following administration of K201.

Claims

WHAT IS CLAIMED IS:
1. A method for treating a subject, comprising: administering multiple doses of K201 over a multi-day period to a subject suffering from or at risk of cardiac arrhythmia according to a dosing schedule, wherein the dosing schedule requires no more than three temporally-spaced doses per day.
2. The method of Claim 1, wherein the dosing schedule requires no more than two doses per day.
3. The method of Claim 1, wherein the doses of K.201 are provided in an oral dosage form.
4. The method of Claim 1 , wherein the subject has congestive heart failure.
5. The method of Claim4, wherein the heart failure is systolic heart failure.
6. The method of Claim 4, wherein the heart failure is diastolic heart failure.
7. A method for treating a subject, comprising: providing a formulation of K201 for administration to a subject, wherein the subject is suffering from or at risk for arrhythmia, wherein upon administration to the subject, the formulation provides a peak blood concentration of K201 (Cmax) at a first time Tl (measured from the administration), after which the blood concentration of K201 decreases to a minimum effective concentration (Cmec) at a second time T2 (measured from the administration); and administering multiple temporally-spaced doses of the K201 formulation to the subject over multiple days according to a dosing schedule, wherein the spacing between at least some doses is an interval T3, wherein T3 is greater than T2.
8. The method of Claim 7, wherein T3 is selected such that the subject has a blood level of the K201 metabolite Mil at T3 such that either the level of Mil or the combined levels of Mil and K201 at T3 are effective to treat or prevent arrhythmia in the subject.
9. The method of Claim 7, wherein the subject has heart failure.
10. The method of Claim 7, wherein the formulation of K201 is an oral dosage form.
1 1. The method of Claim 9, wherein the heart failure is systolic heart failure.
12. The method of Claim 9, wherein the heart failure is diastolic heart failure.
13. A method of treating or preventing a cardiac arrhythmia in a subject in need thereof, comprising: providing a therapeutically effective amount of K201 or a pharmaceutically acceptable salt, ester, or amide thereof to a subject suffering from or at risk of cardiac arrhythmia; informing the subject or medical care worker that administration can provide antiarrhythmic effects for a period of time following administration of the composition, wherein the time period exceeds the half life of K201 ; and administering the K201 to the subject.
14. The method of Claim 13, wherein said subject has congestive heart failure.
15. The method of Claim 14, wherein the heart failure is systolic heart failure.
16. The method of Claim 14, wherein the heart failure is diastolic heart failure.
17. The method of Claim 13, wherein the time period is at least six hours.
18. A method of treating a subject, comprising: designing a course of therapy that is intended to achieve antiarrhythmic effects for at least a predetermined period, wherein the course of therapy includes the administration of more than one dose of a therapeutically effective amount of K201 or a pharmaceutically acceptable salt, ester, or amide thereof, and wherein when the time period between the sequential doses of K201 exceeds the half-life of K201 ; and administering K201 to the subject according to the designed course of therapy, wherein the subject has or is at risk of developing a cardiac arrhythmia.
19. The method of Claim 18, wherein said subject has congestive heart failure.
20. The method of Claim 19, wherein the heart failure is systolic heart iailure.
21. The method of Claim 19, wherein the heart failure is diastolic heart failure.
22. The method of Claim 18, wherein the time period is at least six hours.
23. A method of treating or preventing a cardiac disorder in a subject in need thereof, comprising: providing a therapeutically effective amount of K201 or a pharmaceutically acceptable salt, ester, or amide thereof to a subject having or at risk of a cardiac disorder; informing the subject or medical care worker that administration can provide antiarrhythmic effects for a period of time following administration of the composition, wherein the time period exceeds the half life of K201 ; and administering the K201 to the subject.
24. The method of Claim 23, wherein said subject has congestive heart failure.
25. The method of Claim 24, wherein the heart failure is systolic heart failure.
26. The method of Claim 24, wherein the heart failure is diastolic heart failure.
27. The method of Claim 23, wherein the time period is at least six hours.
28. The method of Claim 23, wherein the cardiac disorder is an atrial cardiac rhythm disorder selected from the group consisting of atrial fibrillation, atrial flutter, or other supraventricular tachycardia.
29. The method of Claim 23, wherein the cardiac disorder is a ventricular cardiac rhythm disorder selected from the group consisting of ventricular tachycardia and ventricular fibrillation.
30. The method of Claim 29, wherein the ventricular cardiac rhythm disorder is a ventricular tachycardia selected from the group consisting of Torsades des Pointes, catecholaminergic polymorphic ventricular tachycardia, and monomorphic ventricular tachycardia.
31. The method of Claim 29, wherein said cardiac disorder is sudden cardiac death.
32. The method of Claim 29, wherein said cardiac disorder is acute and/or chronic cardiomyopathy.
33. The method of Claim 29, wherein said cardiac disorder is acute coronary syndrome.
34. The method of Claim 33, wherein said acute coronary syndrome is selected from the group consisting of myocardial infarction and angina.
35. The method of Claim 23, wherein said cardiac disorder is acute and/or chronic hypertension.
36. The method of Claim 35, wherein said acute and/or chronic hypertension is catecholamine-induced hypertension.
37. The method of Claim 23, wherein said cardiac disorder is pulmonary edema.
38. The method of Claim 23, wherein said cardiac disorder is chronic obstructive pulmonary disease.
39. A method for treating a subject, comprising: administering multiple doses of K201 over a multi-day period to a subject suffering from or at risk of developing congestive heart failure according to a dosing schedule, wherein the dosing schedule requires no more than three temporally-spaced doses per day.
40. The method of Claim 39, wherein the heart failure is systolic heart failure.
41. The method of Claim 39, wherein the heart failure is diastolic heart failure.
42. A method for treating a subject, comprising: providing a formulation of K201 for administration to a subject, wherein upon administration to the subject, the formulation provides a peak blood concentration of K201 (Cmax) at a first time Tl (measured from the administration), after which the blood concentration of K201 decreases to a minimum effective concentration (Cmec) at a second time T2 (measured from the administration), wherein the subject is suffering from or at risk of developing congestive heart failure; and administering multiple temporally-spaced doses of the K201 formulation to the subject over multiple days according to a dosing schedule, wherein the spacing between doses is an interval T3, wherein T3 is greater than T2.
43. The method of Claim 42, wherein the heart failure is systolic heart failure.
44. The method of Claim 42, wherein the heart failure is diastolic heart failure.
45. A method of treating subject having or at risk of developing a congestive heart failure, comprising: designing a course of therapy that is intended to treat or prevent the symptoms of congestive heart failure for at least a predetermined period, wherein the course of therapy includes the administration of more than one dose of a therapeutically effective amount of K201 or a pharmaceutically acceptable salt, ester, or amide thereof, and wherein when the time period between the sequential doses of K201 exceeds the half-life of K201.
46. The method of Claim 42, wherein the heart failure is systolic heart failure.
47. The method of Claim 42, wherein the heart failure is diastolic heart failure.
PCT/US2009/039536 2009-04-03 2009-04-03 Improved methods of administration of k201 (jtv-519) (4-[3-{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy 2, 3, 4, 5-tetrahydro-1, 4-benzothiazepine monohydrochloride) WO2010114562A1 (en)

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