Pharmaceutical compositions of (R)-1-(2,2-difluorobenzo[D][1,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1) cyclopropanecarbox-amide and administration thereof
A pharmaceutical composition comprising Compound 1, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, and at least one excipient selected from: a filler, a disintegrant, a surfactant, a glidant and a lubricant, the composition being suitable for oral administration to a patient in need thereof to treat a CFTR mediated disease such as Cystic Fibrosis. Methods for treating a patient in need thereof include administering the pharmaceutical composition of Compound 1 are also disclosed.
1. A method for treating cystic fibrosis in a patient, comprising coadministering:
a) a pharmaceutical composition comprising 5 to 250 mg of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound 1) and a pharmaceutically acceptable carrier, wherein Compound 1 is in a spray dried dispersion; and
b) another pharmaceutical composition comprising 100 to 300 mg N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2) and a pharmaceutically acceptable carrier;
wherein the patient has a ΔF508 or G551D cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation and a second CFTR gene mutation selected from R117H, A455E, 2789+5G→A, and 3849+10kbC→T;
wherein the pharmaceutical composition of step (a) is administered concurrently with the pharmaceutical composition of step (b).
2. The method of claim 1 , wherein Compound 1 is substantially amorphous, wherein less than 15% of Compound 1 is in crystalline form.
3. The method of claim 2 , wherein less than 10% of Compound 1 is in crystalline form.
4. The method of claim 3 , wherein less than 5% of Compound 1 is in crystalline form.
5. The method of claim 4 , wherein less than 1% of Compound 1 is in crystalline form.
6. The method of claim 1 , wherein Compound 1 is present in an amount of about 100 mg.
7. The method of claim 1 , wherein the pharmaceutical composition of step (a) and the pharmaceutical composition of step (b) are administered once a day.
8. The method of claim 1 , wherein 150 mg of Compound 2 is administered.
9. The method of claim 1 , wherein the method comprises administering an additional therapeutic agent.
10. The method of claim 9 , wherein the additional therapeutic agent is a mucolytic agent, bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 2, or a nutritional agent.
11. The method of claim 9 , wherein the additional therapeutic agent is a CFTR modulator other than Compound 2.
12. The method of claim 1 , wherein the second CFTR gene mutation is A455E.
13. The method of claim 1 , wherein the second CFTR gene mutation is 2789+5G→A.
14. The method of claim 1 , wherein the second CFTR gene mutation is 3849+10kbC→T.