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US-20260124393-A1 - DOWN TITRATION LOADING OF SOTALOL INTRAVENOUSLY

US20260124393A1US 20260124393 A1US20260124393 A1US 20260124393A1US-20260124393-A1

Abstract

The present invention relates to a method of loading sotalol intravenously that starts with the highest approved doses, evaluates the QTc effects, and selects the highest does that is represented by a maximum serum drug concentration that does not excessively prolong the QTc interval on the electrocardiogram. The method further relates to down titration if needed.

Inventors

  • John Charin Somberg

Assignees

  • ACADEMIC PHARMACEUTICALS, INC.

Dates

Publication Date
20260507
Application Date
20241106

Claims (20)

  1. 1 . A method of loading sotalol, comprising: a) administering intravenously (IV) to a patient in need thereof, over 1 hour, a loading dose based on the calculated highest oral target dose based on weight, with the IV loading dose being adjusted for renal function as shown in Table A; TABLE A Minimum delay Next oral Discharge 1 hour IV to first dosing (hours CrCL loading oral dose interval after IV (mL/min) dose (mg) (hours) (hours) start) Target Dose 120 mg, Patient Weight ≤90 kg >90 90 4 12 9-12 h (1 oral dose), 12-23 h (2 oral doses) >60-90 125 4 12 9-12 h (1 oral dose), 12-23 h (2 oral doses) >30-60 112.5 6 24 31-39 10-30 112.5 12 48 61-69 Target Dose 160 mg, Patient Weight >90 kg >90 120 4-8 12 9-12 h (1 oral dose), 12-23 h (2 oral doses) >60-90 165 4-8 12 9-12 h (1 oral dose), 12-23 h (2 oral doses) >30-60 150 6 24 31-39 10-30 150 12 48 61-69 b) optionally, slowing the infusion rate if the QTc increases to >500 msec and/or stopping the infusion if there is persistent QTc prolongation >500 msec; c) if the QTc is <500 msec at 4 hours after completion of the IV loading dose, administering a first oral dose of sotalol based on the highest target oral dose selected for step a), provided that if the patient has a creatinine clearance of ≤60 mL/min then the timing of the first oral dose is delayed as described in Table A: d) if the QTc is <500 msec at 4 hours after administering the first oral dose, discharging the patient; e) alternatively, if the QTc is <500 msec at 12 hours the first oral dose, administering a second oral dose of sotalol based on the highest target oral dose selected for step a), provided that if the patient has a creatinine clearance of ≤60 mL/min then the timing of the second oral dose is delayed as described in Table A; and, f) discharging the patient after the second oral dose, the timing of which is described in Table A.
  2. 2 . The method of claim 1 , further comprising: in step a), measuring the QTc interval every 15 minutes.
  3. 3 . The method of claim 1 , further comprising: measuring the QTc at one or more of 2 and 4 hours after completion of the IV.
  4. 4 . The method of claim 1 , further comprising: measuring the QTc at one or more of 2, 4, and 8 hours after administering the first oral dose.
  5. 5 . The method of claim 1 , further comprising: measuring the QTc at one or more of 2, 4, 6, 8, and 12 hours after administering the second oral dose.
  6. 6 . The method of claim 1 , wherein the patient's QTc increases to >500 msec and the infusion rate is slowed.
  7. 7 . The method of claim 6 , wherein the QTc>500 msec remains after slowing the infusion rate and the infusion is stopped.
  8. 8 . The method of claim 6 , wherein the infusion rate is slowed to 1.25-2 h.
  9. 9 . The method of claim 1 , wherein the second oral dose is administered 12 hours after the first oral dosage, provided that if the patient has a creatinine clearance of ≤60 mL/min then the timing of the second oral dose is delayed as described in Table A.
  10. 10 . The method of claim 1 , wherein the patient is discharged 9-17 hours after initiation of the IV dose, provided that if the patient has a creatinine clearance of ≤60 mL/min then these times are delayed as described in Table A.
  11. 11 . The method of claim 1 , wherein the patient is discharged 9 hours after initiation of the IV dose, having received 1 oral dose of sotalol.
  12. 12 . The method of claim 1 , wherein the patient is discharged 13 hours after initiation of the IV dose, having received 1 oral dose of sotalol.
  13. 13 . The method of claim 1 , wherein the patient is discharged 17 hours after initiation of the IV dose, having received 2 oral doses of sotalol.
  14. 14 . The method of claim 1 , wherein the patient is discharged 21-23 hours after initiation of the IV dose, having received 2 oral doses of sotalol.
  15. 15 . The method of claim 1 , wherein the patient has exhibited excessive QTc prolongation (>500 msec) during the IV and the first oral dose is reduced to 80 mg if 120 was originally targeted or 120 mg if 160 mg was originally targeted.
  16. 16 . The method of claim 15 , wherein oral sotalol is stopped if the patient's QTc remains excessive with the reduced dose.
  17. 17 . The method of claim 1 , wherein the patient has exhibited excessive QTc prolongation (>500 msec) after the first oral dose and the second oral dose is reduced to 80 mg if 120 was originally targeted or 120 mg if 160 mg was originally targeted.
  18. 18 . The method of claim 17 , wherein oral sotalol is stopped if the patient's QTc remains excessive with the reduced dose.
  19. 19 . The method of claim 17 , wherein the patient is discharged 21-25 hours after initiation of the IV dose, having received 2 oral doses of sotalol.
  20. 20 . The method of claim 1 , wherein the discharged patient is prescribed oral sotalol twice daily (BID) at the same dose as the second oral dose.

Description

BACKGROUND OF THE INVENTION Sotalol is an anti-arrhythmic agent primarily used to prevent recurrence of highly symptomatic atrial fibrillation or atrial flutter (AF/AFC). Loading of sotalol has been routinely performed by oral drug administration over 3 days of in hospital observation to determine the effect of a given oral dose on the QTc interval. QTc prolongation on the ECG represents prolongation in cardiac repolarization. Prolongation in cardiac repolarization is the primary mechanism by which sotalol prevents AF/AFL recurrence. However, excessive prolongation of ventricular repolarization as seen as prolongation of the QTc interval can precipitate cardiac arrhythmias developing in the ventricular muscle of the heart. These arrhythmias may be ventricular tachycardia (VT) or ventricular fibrillation (VF). They are often proceeded by a fast ventricular arrhythmia termed torsade de pointe VT, that may be life threatening or degenerate into polymorphic VT or VF. Studies have reported that QTc prolongation in excess of 500 msec or 550 msec in patients with conduction abnormalities increases the frequency of these serious arrhythmias. Thus the U.S. FDA has recommended stopping sotalol therapy or reducing the dose of sotalol that would result in a reduced QTc prolongation. To reduce the time in hospital loading, IV administration of sotalol has been utilized to achieve a maximum steady state concentration of a selected dose in a shortened period of time permitting the evaluation of the effects of this concentration on the QTc interval and thus the potential for life threatening arrhythmias. Somberg (U.S. Pat. No. 10,512,620B1) has taught to load sotalol IV to the low target dose of sotalol that is 80 mg and then if tolerated to escalate to higher doses of oral sotalol 120 and 160 mg. This dose escalation initially takes 24 hours. If dose is tolerated (QTc prolongation acceptable) then patients can be brought back to the hospital for further loading with dose escalation initiated again, prolonging the in-hospital loading to 2, 3, or 4 days. What usually occurs is loading to 80 mg and discharge at the lowest and least effective dose of sotalol employed for chronic oral dosing. Given the additional time requirements for up titration to higher doses, the additional titration is often not undertaken. The lack of up titration of sotalol initially leads to patients often receiving inadequate doses of sotalol as maintenance therapy to prevent recurrence of AF. The inevitable recurrence of arrhythmias requiring hospitalization leading to increased dosing or switching to an alternative drug therapy is inconvenient but more serious is the development of an AF/AFL recurrence which can lead to embolization and stroke with severe consequences to the patient. It would be beneficial to find a way to achieve a higher dose of sotalol without a second titration/hospital stay (up titration). It would also be beneficial to avoid re-hospitalization due to a recurrence of AF/AFL because of inadequate sotalol dosing. SUMMARY OF THE INVENTION Accordingly, in some aspects, there are described methods of intravenous (IV) loading of sotalol starting at the calculated highest tolerated dose and down titrating if QT prolongation is excessive. In some aspects, there are described novel methods of IV loading of sotalol starting at the calculated highest tolerated dose, followed by oral dosing 4 hours after completion of the IV loading dose. In some aspects, there are described novel methods of initiating sotalol by IV loading starting at the calculated highest tolerated dose, following by oral dosing, and discharging a patient about 9-17 hours after initiating the IV. These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that the presently claimed methods of starting sotalol titration at the calculated highest tolerated dose and down-titrating where necessary. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows an example of a pharmacokinetic sequence for an intravenous loading dose followed by first and second oral doses. FIG. 2 shows a flow chart for the IV initiation of sotalol at 120 mg and creatinine clearance of >90 mL/min and down titrating if QT prolongation is excessive. DETAILED DESCRIPTION OF THE INVENTION All references cited herein are hereby incorporated in their entirety herein by reference. Definitions a. BID: twice daily;b. BP: blood pressure;c. HR: heart rate;d. IV: intravenous or intravenously;e. PO: per os, orally;f. QT interval: time from the start of the Q wave to the end of the T wave in an electrocardiogram; and,g. QTc: corrected QT interval for heart rate. Method of Sotalol IV Loading The IV loading of sotalol is typically required to be initiated in a facility that can provide continuous ECG monitoring and cardiac resuscitation. Personnel are typically trained in the management of serious life-threatening ventricular arrhythmias. In