Method of treating conditions related to the pgi2 receptor

Abstract

Provided in some embodiments are titration packages, kits, and methods of treating pulmonary arterial hypertension comprising prescribing and/or administering to a patient in need thereof 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, over a period of no more than about nine weeks until an optimized dose is administered.

What is claimed is: 
     
         1 . A method of treating pulmonary arterial hypertension comprising
 prescribing and/or administering to a patient in need thereof 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof,   wherein the Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is administered via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, until an optimized dose is administered.   
     
     
         2 . The method of  claim 1 , wherein the titration scheme comprises prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at an initial dose equivalent to 0.01 mg of Compound 1 twice daily for about one week and, provided that the patient tolerates the initial dose, increasing the dose. 
     
     
         3 . The method according to  claim 1  or  2 , wherein the titration scheme further comprises prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at said increased dose for about one week and, provided that the patient tolerates the increased dose, further increasing the dose. 
     
     
         4 . The method according to  claim 3 , wherein the titration scheme comprises a cycle of prescribing and/or administering the increased dose for a period of about one week and then further increasing the dose, wherein the cycle is repeated so long as the patient tolerates the further increased dose, until an optimized dose is administered. 
     
     
         5 . A method of determining an optimized dose for a patient in need of treatment of pulmonary arterial hypertension comprising:
 prescribing and/or administering to the patient 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and   increasing the dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, until the optimized dose for the patient is administered.   
     
     
         6 . A method of determining an optimized dose for the patient in need of treatment with 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, comprising:
 prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to the patient at an initial dose equivalent to 0.01 mg of Compound 1 twice daily for about one week; and   determining whether the patient tolerates the initial dose;   wherein if the patient tolerates the initial dose, the dose is increased by an amount equal to a first incremental value; and   wherein if the patient does not tolerate the initial dose, the optimized dose for the patient is less than the equivalent of 0.01 mg of Compound 1 twice daily.   
     
     
         7 . The method of  claim 6 , further comprising:
 prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to the patient at the increased dose for about one week; and   determining whether the patient tolerates the increased dose;   wherein if the patient tolerates the increased dose, the dose is further increased by an amount equal to a second incremental value, wherein the second incremental value is the same or different from the first incremental value;   wherein if the patient does not tolerate the increased dose, the optimized dose for the patient is equal to the difference between the increased dose and the first incremental value.   
     
     
         8 . The method of any one of  claims 1  to  7 , further comprising prescribing and/or administering the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to the patient. 
     
     
         9 . The method of any one of  claims 1  to  7 , wherein the up-titration is performed over a period of about 9 weeks. 
     
     
         10 . The method of any one of  claims 1  to  7 , wherein the amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, administered to the patient is increased at weekly intervals until the optimized dose is administered. 
     
     
         11 . The method of any one of  claims 1  to  7 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.01 mg of Compound 1 twice daily. 
     
     
         12 . The method of any one of  claims 1  to  7 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.02 mg of Compound 1 twice daily. 
     
     
         13 . The method of any one of  claims 1  to  7 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.03 mg of Compound 1 twice daily. 
     
     
         14 . The method of any one of  claims 1  to  7 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.04 mg of Compound 1 twice daily. 
     
     
         15 . The method of any one of  claims 1  to  7 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.06 mg of Compound 1 twice daily. 
     
     
         16 . The method of any one of  claims 1  to  7 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.08 mg of Compound 1 twice daily. 
     
     
         17 . The method of any one of  claims 1  to  7 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.1 mg of Compound 1 twice daily. 
     
     
         18 . The method of any one of  claims 1  to  7 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.2 mg of Compound 1 twice daily. 
     
     
         19 . The method of any one of  claims 1  to  7 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.3 mg of Compound 1 twice daily. 
     
     
         20 . The method of any one of  claims 1  to  7 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.6 mg of Compound 1 twice daily. 
     
     
         21 . The method of any one of  claims 1  to  7 , wherein the Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is administered orally. 
     
     
         22 . The method of  claim 21 , wherein the Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a capsule or tablet suitable for oral administration. 
     
     
         23 . The method of any one of  claims 1  to  22 , wherein the Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is Compound 1, or a hydrate or solvate thereof. 
     
     
         24 . The method of any one of  claims 1  to  22 , wherein the Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is Compound 1. 
     
     
         25 . The method of any one of  claims 1  to  24  wherein pulmonary arterial hypertension (PAH) is selected from:
 idiopathic PAH; 
 familial PAH; 
 PAH associated with a collagen vascular disease selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; 
 PAH associated with a congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD) and patent ductus arteriosus in a patient: 
 PAH associated with portal hypertension; 
 PAH associated with HIV infection; 
 PAH associated with ingestion of a drug or toxin; 
 PAH associated with hereditary hemorrhagic telangiectasia; 
 PAH associated with splenectomy; 
 PAH associated with significant venous or capillary involvement; 
 PAH associated with pulmonary veno-occlusive disease (PVOD); and 
 PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient. 
 
     
     
         26 . A titration package for enabling compliance with a regimen of changing dosage of medication over a period of time, wherein the medication is 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, the package comprising:
 a backing having an array of receivers, said array including a plurality of columns and a plurality of rows;   a plurality of sets of solid dosage forms, each solid dosage form in a set having a common dose of the medication and a different dose than a solid dosage form of a different set, each set being disposed in receivers of one of an adjacent row and an adjacent column; different sets of solid dosage forms are disposed in different rows, each row being indicated as a successive time period, each column being indicated as a different day of the time period, sets of solid dosage forms having increased doses being disposed in receivers of rows indicated as successive time periods; and indicia disposed adjacent the columns and rows for displaying common days and successive time periods.   
     
     
         27 . A kit comprising a titration package of  claim 26  and instructions indicating that the medication is to be administered to a patient in need of treatment of pulmonary arterial hypertension. 
     
     
         28 . A method of treating pulmonary arterial hypertension comprising providing a kit of  claim 27  to patient in need thereof. 
     
     
         29 . A pharmaceutical composition comprising an amount of 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.01 mg to 0.6 mg of Compound 1. 
     
     
         30 . A pharmaceutical composition comprising an amount of 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.01 mg to 0.3 mg of Compound 1. 
     
     
         31 . The pharmaceutical composition of  claim 29  or  30 , wherein the composition is in the form of a tablet. 
     
     
         32 . The pharmaceutical composition of  claim 29  or  30 , wherein the composition is in the form of a capsule. 
     
     
         33 . A method for the treatment of PAH, the method comprising prescribing and/or administering to the patient a pharmaceutical composition comprising an amount of 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.01 mg to 0.6 mg of Compound 1, twice daily. 
     
     
         34 . A method for the treatment of PAH, the method comprising prescribing and/or administering to the patient a pharmaceutical composition comprising an amount of 2-(((1r,4r)-4-((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.01 mg to 0.3 mg of Compound 1, twice daily. 
     
     
         35 . The method of  claim 33  or  34 , wherein the composition is in the form of a tablet. 
     
     
         36 . The method of  claim 33  or  34 , wherein the composition is in the form of a capsule. 
     
     
         37 . The method of any one of  claims 1  to  3 , wherein the titration scheme comprises a cycle of
 1) prescribing and/or administering for a period of about one week a dose that is higher by an incremental value than the dose for a previous period, and 
 2) determining whether the patient tolerates the higher dose for such period of about one week;
 wherein the cycle of steps 1) and 2) is repeated so long as the patient tolerates the higher dose, wherein the incremental value at every repetition of the cycle is the same or different from a previous incremental value; 
 wherein if the patient does not tolerate the higher dose, the optimized dose for the patient is equal to the difference between the higher dose and the incremental value for the last cycle repetition. 
 
 
     
     
         38 . The method of  claim 5 , wherein the method comprises prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, over more than one period each of about one week, wherein the method comprises a cycle of
 1) prescribing and/or administering for a period of about one week a dose that is higher by an incremental value than the dose for a previous period, and   2) determining whether the patient tolerates the higher dose for such period of about one week;   wherein the cycle of steps 1) and 2) is repeated so long as the patient tolerates the higher dose, wherein the incremental value at every repetition of the cycle is the same or different from a previous incremental value;   wherein if the patient does not tolerate the higher dose, the optimized dose for the patient is equal to the difference between the higher dose and the incremental value for the last cycle repetition.   
     
     
         39 . The method of  claim 37  or  38 , wherein the higher dose administered is equal to an amount administered twice daily that is higher than the amount administered twice daily for a previous period is, and determining whether the patient tolerates the higher dose comprises:
 a) determining whether the patient tolerates the higher amount administered twice daily; 
 b) if the patient does not tolerate the higher amount administered twice daily, administering the higher amount once daily to the patient; 
 c) if the patient tolerates the higher amount administered once daily, re-administering the higher amount twice daily to the patient; and 
 d) determining if the patient tolerates the higher amount re-administered twice daily. 
 
     
     
         40 . The method of  claim 37 , wherein the up-titration is performed over a period of about 9 weeks. 
     
     
         41 . The method of any one of  claims 37  to  40 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.01 mg of Compound 1 twice daily. 
     
     
         42 . The method of any one of  claims 37  to  40 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.02 mg of Compound 1 twice daily. 
     
     
         43 . The method of any one of  claims 37  to  40 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.03 mg of Compound 1 twice daily. 
     
     
         44 . The method of any one of  claims 37  to  40 , wherein the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is equivalent to 0.1 mg of Compound 1 twice daily.