Combination therapy for treating pulmonary hypertension
The present disclosure describes a method of treating pulmonary disorders, such as pulmonary arterial hypertension, using a combination of a PDGF receptor kinase inhibitor, PDEV inhibitor, and an endothelin receptor antagonist. The compounds can inhibit cell growth and proliferation and target the underlying pathology of PAH.
1. A method of treating a condition, the method comprising administering to a subject in need thereof:
a) a therapeutically-effective amount of a tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor is of the formula:
or a pharmaceutically-acceptable salt thereof;
b) a therapeutically-effective amount of a phosphodiesterase type 5 (PDEV) inhibitor selected from the group consisting of sildenafil, tadalafil, vardenafil, and a pharmaceutically-acceptable salt of any of the foregoing; and
c) therapeutically-effective amount of an endothelin receptor antagonist, wherein the endothelin receptor antagonist is ambrisentan, or a pharmaceutically-acceptable salt thereof, wherein the condition is pulmonary arterial hypertension.
2. The method of claim 1 , wherein the subject is human.
3. The method of claim 1 , wherein the PDEV inhibitor is sildenafil or a pharmaceutically-acceptable salt thereof.
4. The method of claim 1 , wherein the PDEV inhibitor is tadalafil or a pharmaceutically-acceptable salt thereof.
5. The method of claim 1 , wherein the PDEV inhibitor is vardenafil or a pharmaceutically-acceptable salt thereof.
6. The method of claim 1 , wherein the administration of the tyrosine kinase inhibitor is by inhalation.
7. The method of claim 1 , wherein the administration of the tyrosine kinase inhibitor is by an inhaler.
8. The method of claim 1 , wherein the administration of the tyrosine kinase inhibitor is by a nebulizer.
9. The method of claim 1 , wherein the administration of the tyrosine kinase inhibitor is by an atomizer.
10. The method of claim 1 , wherein the administration of the PDEV inhibitor and endothelin receptor antagonist is oral.
11. The method of claim 1 , wherein the therapeutically-effective amount of the tyrosine kinase inhibitor is from about 0.25 mg/kg to about 1 mg/kg per day.
12. The method of claim 1 , wherein the therapeutically-effective amount of the PDEV inhibitor is from about 20 mg to about 40 mg per day.
13. The method of claim 1 , wherein the therapeutically-effective amount of the endothelin receptor antagonist is about 5 mg to about 10 mg per day.
14. The method of claim 1 , wherein the tyrosine kinase inhibitor is formulated as a dry powder.
15. The method of claim 1 , wherein the therapeutically-effective amount of the tyrosine kinase inhibitor is about 0.25 mg/kg/day to about 0.5 mg/kg/day, the therapeutically-effective amount of the PDEV inhibitor is about 1 mg/kg, and the therapeutically-effective amount of the endothelin receptor antagonist is about 1 mg/kg.
16. The method of claim 1 , wherein the tadalafil or a pharmaceutically-acceptable salt thereof and ambrisentan or a pharmaceutically-acceptable salt thereof are administered orally.
17. The method of claim 15 , wherein the tyrosine kinase inhibitor is administered by inhalation.