INTRAVENOUS AND ORAL DOSING OF A DIRECT-ACTING AND REVERSIBLE P2Y12 INHIBITOR
The invention provides methods and compositions for rapid and reversible inhibition of platelet aggregation in human subjects in need thereof by administering compounds of the formula: alone or in combination with a second agent which can be aspirin or a thrombolytic agent.
1 . A method of inhibiting ADP-induced platelet aggregation in a human subject in need thereof, said method comprising intravenously administering to the subject a pharmaceutical composition comprising a compound of the formula:
and at least one pharmaceutically acceptable excipient or carrier and wherein the composition is formulated for intravenous administration.
2 . The method of claim 1 , wherein the composition is formulated as a unit dose containing from 1 to 50 mg of the compound.
3 . The method of claim 2 , wherein the unit dose contains from 5 to 40 mg of the compound.
4 . The method of claim 3 , wherein the unit dose contains from 10 to 30 mg of the compound.
5 . The method of claim 4 , wherein the unit dose contains from 15 to 25 mg of the compound.
6 . The method of claim 5 , wherein the unit dose contains about 20 mg of the compound.
7 . The method of claim 1 , wherein the unit dose contains about 25 mg to 45 mg of the compound.
8 . The method of claim 1 , wherein the subject has an acute coronary syndrome.
9 . The method of claim 1 , wherein the subject is need of a reversible inhibition of ADP-induced platelet aggregation.
10 . The method of claim 9 , wherein the subject is to be scheduled for surgery or other medical procedure associated with bleeding within five days of the administration.
11 . The method of claim 1 , wherein the composition is administered as a bolus over a period of less than 20 minutes.
12 . The method of claim 11 , wherein the composition is administered as a bolus over a period of less than 10 minutes.
13 . The method of claim 12 , wherein the composition is administered as a bolus over a period of less than 5 minutes.
14 . The method of claim 1 , wherein the subject is further administered aspirin.
15 . The method of claim 14 , wherein the aspirin is administered orally.
16 . The method of claim 1 , wherein the subject was predosed with aspirin.
17 . The method of claim 1 , wherein the compound is formulated as a pharmaceutically acceptable salt.
18 . The method of claim 17 , wherein the salt is a sodium or potassium salt.
19 . The method of claim 1 , wherein a substantial degree of the platelet aggregation inhibition develops in the subject within 5 minutes after the composition is administered.
20 . The method of claim 1 , wherein a substantial degree of the platelet aggregation inhibition develops in the subject within 2 minutes after the composition is administered.
21 . The method of claim 19 , wherein the substantial degree of the platelet aggregation inhibition is at least 50% as determined by ADP-induced platelet aggregation values measured at six minutes.
22 . The method of claim 19 , wherein the substantial degree of the platelet aggregation inhibition is at least 70% as determined by ADP-induced platelet aggregation values measured at six minutes.
23 . The method of claim 1 , wherein the substantial degree of the platelet aggregation inhibition is at least 90% as determined by ADP-induced platelet aggregation values measured at six minutes.
24 . The method of claim 1 , wherein the inhibition is rapid in onset.
25 . The method of claim 1 , wherein a thrombolytic agent is also administered.
26 . The method of claim 25 , wherein the thrombolytic agent is TPA, SK, or TNK.
27 . A method of inhibiting ADP-induced platelet aggregation inhibition in a human subject in need thereof, said method comprising orally administering to the subject a pharmaceutical composition comprising a compound of the formula:
and at least one pharmaceutically acceptable excipient or carrier and wherein the composition is formulated for oral administration.
28 . The method of claim 27 , wherein the composition is formulated as a unit dose containing from 1 to 800 mg of the compound.
29 . The method of claim 28 , wherein the unit dose contains from 20 to 200 mg of the compound.
30 . The method of claim 29 , wherein the unit dose contains from 50 to 150 mg of the compound.
31 . The method of claim 30 , wherein the unit dose contains from 10 to 50 mg of the compound.
32 . The method of claim 31 , wherein the unit dose contains about 20 to 40 mg of the compound.
33 . The method of claim 27 , wherein the subject has an acute coronary syndrome.
34 . The method of claim 27 , wherein the subject is need of a reversible inhibition of ADP-induced platelet aggregation.
35 . The method of claim 33 , wherein the subject is to be scheduled for surgery or other medical procedure associated with bleeding within five days of the administration.
36 . The method of claim 27 , wherein the composition is formulated as a solid.
37 . The method of claim 27 , wherein the composition is administered as a tablet, capsule, or powder.
38 . The method of claim 37 , wherein the composition is administered as a liquid.
39 . The method of claim 27 , wherein the subject is further administered aspirin.
40 . The method of claim 39 , wherein the aspirin is administered orally.
41 . The method of claim 27 , wherein the subject was predosed with aspirin.
42 . The method of claim 27 , wherein the compound is formulated as a pharmaceutically acceptable salt.
43 . The method of claim 42 , wherein the salt is a sodium or potassium salt.
44 . The method of claim 27 , wherein a substantial degree of the platelet aggregation inhibition develops in the subject within 1 hour after the composition is administered.
45 . The method of claim 27 , wherein a substantial degree of the platelet aggregation inhibition develops in the subject within 2 hours after the composition is administered.
46 . The method of claim 45 , wherein the substantial degree of platelet aggregation inhibition is at least 50% as determined by ADP-induced platelet aggregation values measured at six minutes.
47 . The method of claim 46 , wherein the substantial degree of platelet aggregation inhibition is at least 70% as determined by ADP-induced platelet aggregation values measured at six minutes.
48 . A pharmaceutical composition comprising a compound of the formula:
and at least one pharmaceutically acceptable excipient or carrier and wherein the composition is formulated for intravenous administration.
49 . The composition of claim 48 , wherein the composition is formulated as a unit dose containing from 1 to 50 mg of the compound.
50 . The composition of claim 49 , wherein the unit dose contains from 5 to 40 mg of the compound.
51 . The composition of claim 50 , wherein the unit dose contains from 10 to 30 mg of the compound.
52 . The composition of claim 51 , wherein the unit dose contains from 15 to 25 mg of the compound.
53 . The composition of claim 52 , wherein the unit dose contains about 20 mg of the compound.
54 . A pharmaceutical composition comprising a compound of the formula:
and at least one pharmaceutically acceptable excipient or carrier and wherein the composition is formulated for oral administration.
55 . The composition of claim 54 , wherein the composition is formulated as a unit dose containing from 1 to 800 mg of the compound.
56 . The composition of claim 55 , wherein the unit dose contains from 20 to 200 mg of the compound.
57 . The composition of claim 56 , wherein the unit dose contains from 50 to 150 mg of the compound.
58 . The composition of claim 57 , wherein the unit dose contains from 10 to 50 mg of the compound.
59 . The composition of claim 58 , wherein the unit dose contains about 20 to 40 mg of the compound.
60 . A compound of the formula
for use in manufacturing a medicament for treating ACS.