Pharmaceutical compositions comprising a ryanodine receptor modulator and uses thereof
The present disclosure provides a modified-release pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, and a pharmaceutically-acceptable excipient. The present disclosure methods of treating conditions associated with RyRs, including, for example, cardiac disorder or disease, a musculoskeletal disorder or disease, cancer associated muscle weakness, malignant hyperthermia, and diabetes.
1. A method of treating catecholaminergic polymorphic ventricular tachycardia, comprising administering to a subject in need thereof a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising in a unit dosage form 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable excipient, wherein when administered to a subject, the pharmaceutical composition provides to the subject a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof at a time between about 2 to about 6 hours after administration.
2. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject a maximum plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof at a time between about 3 to about 4 hours after administration.
3. The method of claim 1 , wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt, wherein the pharmaceutically-acceptable salt is a hemifumarate salt.
4. The method of claim 1 , wherein the unit dosage form is a modified release dosage form.
5. The method of claim 1 , wherein the unit dosage form is a delayed release dosage form.
6. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject an in-vivo mean terminal half-life of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof of about 14 to about 21 hours after administration.
7. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject an accumulation ratio for C max of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof between about 1.4 and about 1.8, wherein said accumulation ratio is calculated as a ratio of C max on Day 28/C max on Day 1, wherein C max is maximum observed plasma concentration.
8. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject an accumulation ratio for AUC of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof between about 1.4 and about 1.8, wherein said accumulation ratio for AUC is calculated as a ratio of AUC tau on Day 28/AUC 0-24 Day 1,
wherein
AUC is area under the concentration-time curve;
AUC tau is area under the concentration-time curve during a dosing interval (tau) at steady-state; and
AUC 0-24 is area under the concentration-time curve, from time 0 to 24 hours post-dose.
9. The method of claim 1 , wherein when administered to the subject, the pharmaceutical composition provides to the subject a steady-state plasma concentration of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or the pharmaceutically-acceptable salt thereof or a pharmaceutically-acceptable ion thereof in a range of about 3 to about 7 days after initial administration.
10. The method of claim 1 , wherein the unit dosage form is suitable for oral administration.
11. The method of claim 1 , wherein the unit dosage form is a gastro-resistant tablet.
12. The method of claim 1 , wherein the catecholaminergic polymorphic ventricular tachycardia is catecholaminergic polymorphic ventricular tachycardia type 1.