DOSE REGIME FOR CAMPTOTHECIN DERIVATIVES
First Claim
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1. A method for inhibiting cancer cell growth in a subject, said method comprising the step of:
- administering to said subject a composition comprising;
at least one compound of formula (I);
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Abstract
The present invention is directed to a method of inhibiting cancer cell growth, comprising administering a pharmaceutical composition to a subject in need thereof. The pharmaceutical composition comprises at least one camptothecin derivative or a pharmaceutically acceptable salt thereof; and at least one PEG phospholipid, and provides a sustained release of topotecan as an active ingredient.
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Citations
41 Claims
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1. A method for inhibiting cancer cell growth in a subject, said method comprising the step of:
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administering to said subject a composition comprising; at least one compound of formula (I);
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2. The method of claim 1,
wherein said pharmaceutically acceptable salt of said compound is TLC388HCl.
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3. The method of claim 1,
wherein said compound is S,S-TLC388, S,R-TLC388, or a mixture thereof.
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4. The method of claim 3,
wherein said compound is a diastereomeric mixture of S,S-TLC388 and S,R-TLC388 in a molar ratio of about 2: - 1 (S,S-TLC388;
S,R-TLC388).
- 1 (S,S-TLC388;
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5. The method of claim 1,
wherein said composition is administered at a level of 1.5 mg/m2 to about 60 mg/m2.
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6. The method of claim 1,
wherein said composition is administered at a level of greater than about 40 mg/m2.
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7. The method of claim 1,
wherein said administering step is repeated weekly.
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8. The method of claim 1,
wherein the Cmax of said topotecan is about 1 ng/mL to about 3720 ng/mL.
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9. The method of claim 1,
wherein the Cmax of said topotecan is about 25 ng/mL to about 3720 ng/mL.
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10. The method of claim 1,
wherein the tmax of said topotecan is about 0.4 hours to about 1.9 hours.
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11. The method of claim 1,
wherein the tmax of said topotecan is about 0.8 hours to about 1.0 hours.
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12. The method of claim 1,
wherein the AUC0-8hr of said topotecan is about 5 hr-ng/mL to about 500 hr-ng/mL.
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13. The method of claim 1,
wherein the AUC0-8hr of said topotecan is about 140 hr-ng/mL to about 500 hr-ng/mL.
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14. The method of claim 1,
wherein the t1/2 of said topotecan is about 4 hours to about 12.5 hours.
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15. The method of claim 1,
wherein the t1/2 of said topotecan is about 4.5 hours to about 7.5 hours.
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16. The method of claim 1,
wherein said composition further provides a sustained release of TLC-U2 to said subject over a period of at least about 8 hours.
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17. The method of claim 16,
wherein the Cmax of said TLC-U2 is about 2 ng/mL to about 105 ng/mL.
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18. The method of claim 16,
wherein the Cmax of said TLC-U2 is about 50 ng/mL to about 110 ng/mL.
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19. The method of claim 16,
wherein the tmax of said TLC-U2 is about 0.2 hours to about 0.7 hours.
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20. The method of claim 16,
wherein the tmax of said TLC-U2 is about 0.3 hours to about 0.5 hours.
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21. The method of claim 16,
wherein the AUC0-8hr of said TLC-U2 is about 2.5 hr-ng/mL to about 115 hr-ng/mL.
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22. The method of claim 16,
wherein the AUC0-8hr of said TLC-U2 is about 70 hr-ng/mL to about 115 hr-ng/mL.
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23. The method of claim 16,
wherein the t1/2 of said TLC-U2 is about 1.5 hours to about 3.5 hours.
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24. The method of claim 16,
wherein the t1/2 of said TLC-U2 is about 1.5 hours to about 3.0 hours.
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25. The method of claim 1,
wherein said composition further provides a sustained release of TLC-U1 to said subject over a period of at least about 8 hours.
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26. The method of claim 25,
wherein the Cmax of said TLC-U1 is about 5 ng/mL to about 450 ng/mL.
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27. The method of claim 25,
wherein the Cmax of said TLC-U1 is about 200 ng/mL to about 450 ng/mL.
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28. The method of claim 25,
wherein the tmax of said TLC-U1 is about 0.2 hours to about 0.7 hours.
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29. The method of claim 25,
wherein the tmax of said TLC-U1 is about 0.3 hours to about 0.6 hours.
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30. The method of claim 25,
wherein the AUC0-8hr of said TLC-U1 is about 5 hr-ng/mL to about 430 hr-ng/mL.
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31. The method of claim 25,
wherein the AUC0-8hr of said TLC-U1 is about 270 hr-ng/mL to about 430 hr-ng/mL.
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32. The method of claim 25,
wherein the t1/2 of said TLC-U1 is about 1.5 hours to about 5.6 hours.
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33. The method of claim 25,
wherein the t1/2 of said TLC-U1 is about 1.8 hours to about 3.5 hours.
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34. The method of claim 1,
wherein said composition further comprises at least one pH adjusting agent.
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35. The method of claim 1,
wherein the molar ratio of said PEG conjugated phospholipid to said compound or pharmaceutically acceptable salt of said compound is about 0.60: - 1 to about 1.00;
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- 1 to about 1.00;
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36. The method of claim 1,
wherein the molar ratio of said PEG conjugated phospholipid to said compound or pharmaceutically acceptable salt of said compound is about 0.70: - 1 to about 0.90;
1.
- 1 to about 0.90;
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37. The method of claim 1,
wherein said composition has a pH less than about 4.
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38. The method of claim 1,
wherein said PEG conjugated phospholipid comprises a PEG moiety having a molecular weight from about 1,000 to about 20,000 daltons.
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39. The method of claim 1,
wherein said PEG conjugated phospholipid is a PEG-DSPE (distearoyl-phosphatidylethanolamine) conjugate.
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40. The method of claim 39,
wherein the PEG-DSPE conjugate is a methoxyl PEG-DSPE conjugate.
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41. The method of claim 1, wherein the composition is administered as a single dose.
Specification