Maintenance of platelet inhibition during antiplatelet therapy

Abstract

A method for reducing or maintaining platelet inhibition in a patient by administering cangrelor prior to an invasive procedure is described. The method of this invention can be used for patients in need of antiplatelet therapy or at risk of thrombosis. The method can further be used in patients who were previously treated with long-acting platelet inhibitors without increasing the risk of excessive bleeding.

1 . A method of maintaining or reducing platelet activity in a patient in need thereof comprising:
 administering to the patient a therapeutically effective amount of cangrelor wherein the patient was previously treated with a long-acting irreversible platelet inhibitor, prior to the patient undergoing an invasive procedure.   
     
     
         2 . The method of  claim 1  wherein administration of cangrelor is at a range of between about 0.1 ug/kg/min to about 5 ug/kg/min. 
     
     
         3 . The method of  claim 1  wherein administration of cangrelor is at a range of between about 0.5 ug/kg/min to about 2 ug/kg/min. 
     
     
         4 . The method of  claim 1  wherein administration of cangrelor is at a range of between about 0.5 ug/kg/min to about 1 ug/kg/min. 
     
     
         5 . The method of  claim 1  wherein administration of cangrelor is about 0.75 ug/kg/min. 
     
     
         6 . The method of  claim 1  wherein the long-acting irreversible platelet inhibitor is a thienopyridine. 
     
     
         7 . The method of  claim 6  wherein the thienopyridine is selected from the group consisting of clopidogrel, ticlopindine, and prasugrel. 
     
     
         8 . The method of  claim 1  wherein administration of cangrelor is within about 3 days of ceasing administration of the long-acting irreversible platelet inhibitor. 
     
     
         9 . The method of  claim 1  wherein cangrelor is continuously administered between about 2 days to about 7 days. 
     
     
         10 . The method of  claim 1  wherein administration of cangrelor is discontinued and allowing platelet activity to return to pre-cangrelor administration levels wherein the measured PRU level is greater than 240, prior to the patient undergoing an invasive procedure. 
     
     
         11 . The method of  claim 1  wherein administration of cangrelor is in an amount to maintain the measured PRU value at less than 240. 
     
     
         12 . The method of  claim 1  wherein cangrelor is concurrently administered with a second therapeutic agent. 
     
     
         13 . The method of  claim 12  wherein said second therapuetic agent is streptokinase, alteplase, reteplase, urokinase, tenecteplase, aspirin, bivalirudin, heparin warfarin, eptifibatide, abciximab or tirofiban. 
     
     
         14 . The method of  claim 1  wherein the risk of bleeding is not increased. 
     
     
         15 . A method for maintaining or reducing platelet activity in a patient comprising: administering to the patient a therapeutically effective amount of cangrelor prior to the patient undergoing an invasive procedure wherein oral administration of platelet inhibition therapy is contra-indicated. 
     
     
         16 . The method of  claim 15  wherein administration of cangrelor is at a range of between about 0.1 ug/kg/min to about 5 ug/kg/min. 
     
     
         17 . The method of  claim 15  wherein administration of cangrelor is at a range of between about 0.5 ug/kg/min to about 2 ug/kg/min. 
     
     
         18 . The method of  claim 15  wherein administration of cangrelor is about 0.75 ug/kg/min. 
     
     
         19 . The method of  claim 15  wherein cangrelor is continuously administered between about 2 days to about 7 days. 
     
     
         20 . The method of  claim 15  wherein administration of cangrelor is discontinued and allowing platelet activity to return to pre-cangrelor administration levels wherein the measured PRU level is greater than 240, prior to the patient undergoing an invasive procedure. 
     
     
         21 . The method of  claim 15  wherein administration of cangrelor is by continuous infusion. 
     
     
         22 . The method of  claim 15  wherein the administration of cangrelor is by a bolus and continuous infusion. 
     
     
         23 . A method of maintaining or reducing platelet activity in a patient in need thereof comprising:
 administering to a patient in need thereof an effective amount of cangrelor prior to undergoing a invasive procedure wherein the measured PRU is maintained at or below about 240 during administration of cangrelor.   
     
     
         24 . The method of  claim 23  wherein the measured PRU is maintained at a range of about 30 to about 240 during administration of cangrelor. 
     
     
         25 . The method of  claim 23  wherein administration of cangrelor is at a range of between about 0.5 ug/kg/min to about 2 ug/kg/min. 
     
     
         26 . The method of  claim 23  wherein administration of cangrelor is about 0.75 ug/kg/min. 
     
     
         27 . The method of  claim 23  wherein administration of cangrelor is within about 3 days of ceasing administration of the long-acting irreversible platelet inhibitor. 
     
     
         28 . The method of  claim 23  wherein cangrelor is continuously administered between about 2 days to about 7 days. 
     
     
         29 . The method of  claim 23  wherein administration of cangrelor is discontinued and allowing platelet activity to return to pre-cangrelor administration levels wherein the measured PRU level is greater than 240, prior to the patient undergoing an invasive procedure. 
     
     
         30 . A method of maintaining or reducing platelet activity comprising:
 administering to a patient in need thereof an effective amount of cangrelor wherein the patient was previously treated with a theinopyridine prior to undergoing an invasive procedure wherein at least about 60% of the platelet activity is inhibited.   
     
     
         31 . The method of  claim 30  wherein administration of cangrelor is at a range of between about 0.1 ug/kg/min to about 5 ug/kg/min. 
     
     
         32 . The method of  claim 30  wherein administration of cangrelor is about 0.75 ug/kg/min. 
     
     
         33 . The method of  claim 30  wherein administration of cangrelor is within about 3 days of ceasing administration of the long-acting irreversible platelet inhibitor. 
     
     
         34 . The method of  claim 30  wherein cangrelor is continuously administered between about 2 days to about 7 days. 
     
     
         35 . The method of  claim 30  wherein administration of cangrelor is discontinued and allowing platelet activity to return to pre-cangrelor administration levels wherein the measured PRU level is greater than 240, prior to the patient undergoing an invasive procedure. 
     
     
         36 . A method of maintaining or reducing platelet activity prior to undergoing an invasive procedure, comprising:
 administering a therapeutically effective amount of cangrelor to a patient in need thereof wherein the PRU level is at or below 240, ceasing administration of cangrelor wherein the PRU levels is similar to pre cangrelor administration levels, prior to said patient undergoing an invasive procedure.   
     
     
         37 . The method of  claim 36  wherein administration of cangrelor is at a range of between about 0.1 ug/kg/min to about 5 ug/kg/min. 
     
     
         38 . The method of  claim 36  wherein administration of cangrelor is about 0.75 ug/kg/min. 
     
     
         39 . The method of  claim 36  wherein cangrelor is continuously administered between about 2 days to about 7 days. 
     
     
         40 . The method of treating or preventing thrombosis comprising:
 administering a therapeutically effective amount of cangrelor to a patient in need thereof where said patient was previously treated with a long-acting irreversible platelet inhibitor, wherein the risk of bleeding is not increased.   
     
     
         41 . The method of  claim 40  wherein administration of cangrelor is at a range of between about 0.1 ug/kg/min to about 5 ug/kg/min. 
     
     
         42 . The method of  claim 40  wherein administration of cangrelor is at a range of between about 0.5 ug/kg/min to about 1 ug/kg/min. 
     
     
         43 . The method of  claim 40  wherein administration of cangrelor is within about 3 days of ceasing administration of the long-acting irreversible platelet inhibitor. 
     
     
         44 . The method of  claim 40  wherein cangrelor is continuously administered between about 2 days to about 7 days. 
     
     
         45 . The method of  claim 40  wherein the measured PRU is maintained below 240 during the administration of cangrelor. 
     
     
         46 . A method of reducing platelet activity in a patient in need thereof comprising:
 administering during the perioperative period to a patient in need of an invasive procedure a therapeutically effective amount of cangrelor wherein the measured PRU is below 240.   
     
     
         47 . The method of  claim 47  wherein cangrelor is continuously administered between about 2 days to about 7 days. 
     
     
         48 . A pharmaceutical composition comprising:
 a therapeutically effective amount of cangrelor formulated with mannitol and sorbitol in combination with an intravenously administrable excipient, wherein said composition maintains the PRU level at or below 240.   
     
     
         49 . The composition of  claim 48  wherein the intravenously administrable excipient is an isotonic infusion media. 
     
     
         50 . The composition of  claim 49  wherein the isotonic infusion media is selected from the group consisting of physiological saline, 0.9% NaCl, phosphate buffered saline, 5% dextrose in water, 0.002% polysorbate 80 (Tween-80.™.) in water or Ringer's.™. solution. 
     
     
         51 . A pharmaceutical composition in intravenous form comprising:
 a therapeutically effective amount of cangrelor with an intravenously administrable carrier for continuous administration to inhibit at least about 60% platelet activity in a patient prior to the patient undergoing an invasive procedure.   
     
     
         52 . The composition of  claim 51  wherein the therapeutically effective amount of cangrelor is in the range of between about 0.1 ug/kg/min to about 5 μg/kg/m in. 
     
     
         53 . The composition of  claim 51  wherein the carrier is selected from the group consisting of physiological saline, 0.9% NaCl, phosphate buffered saline, 5% dextrose in water, 0.002% polysorbate 80 (Tween-80) in water or Ringer's solution. 
     
     
         54 . A method of preparing a cangrelor composition for inhibiting platelet activity comprising:
 dissolving cangrelor or its pharmaceutically acceptable salt by injecting sterile water into a vial containing cangrelor or its pharmaceutically acceptable salt thereof,   preparing an intravenous bag by immediately adding the dissolved cangrelor to an intravenous bag containing infusion media   mixing the intravenous bag thoroughly for administration to a patient wherein the measured PRU of said patient is maintained below about 240.   
     
     
         55 . The composition of  claim 54  wherein the vial contains an amount of cangrelor is in the range of between about 1 mg to about 50 mg. 
     
     
         56 . The composition of  claim 54  wherein the intravenous bag contains from about 250 to 1000 ml of infusion media.