Compositions and methods for achieving sustained therapeutic drug concentrations in a subject
View Patent ↗Provided herein are compounds and methods for achieving a sustained therapeutic effect of small molecule anti-cancer agents when administered in vivo. Sustained Exposure to Active Metabolite with PEG-Irinotecan
1. A method of treating a human subject having metastatic breast cancer, the method comprising administering via a non-continuous dosing regimen to the human subject, a therapeutically effective amount of a pharmaceutical composition comprising a prodrug of structure (I) or a pharmaceutically acceptable salt form thereof:
wherein the non-continuous dosing regimen comprises administering the pharmaceutical composition no more frequently than once every seven days, to thereby maintain sustained therapeutic levels of greater than 0.4 ng/mL of SN-38 in plasma of the subject between dosings.
2. The method of claim 1 , wherein the therapeutic levels of SN-38 remain at or above a concentration in plasma of about 0.5 ng/mL between closings.
3. The method of claim 1 , wherein the dosing regimen comprises administering the pharmaceutical composition at a dosage amount of 145 mg/m 2 irinotecan once every 21 days.
4. The method of claim 1 , wherein the overall nominal average molecular weight of the prodrug ranges from about 10,000 to about 60,000 daltons.
5. The method of claim 4 , wherein the administering occurs at a frequency selected from once every 7 days, once every 14 days, once every 21 days and once every 28 days.
6. The method of claim 1 , wherein the human subject has had no more than two prior treatments with anthracycline and/or taxane-based chemotherapeutics.
7. The method of claim 1 , wherein the administering comprises administering to the human subject a dosage amount of irinotecan ranging from about 70 mg/m 2 to about 300 mg/m 2 .
8. The method of claim 1 , wherein the administering is effective to provide an anti-tumor effect as evidenced by partial tumor regression, arrestment of tumor growth, or by evidence provided by one or more biomarkers.
9. The method of claim 8 , wherein the administering is effective to result in tumor size regression.
10. The method of claim 6 , wherein the prior treatments with anthracycline and/or taxane-based chemotherapeutics were unsuccessful.
11. The method of claim 1 , wherein the pharmaceutical composition is in a form suitable for intravenous administration.
12. The method of claim 11 , wherein the administering is intravenous.
13. The method of claim 1 , wherein the pharmaceutical composition comprises sorbitol and lactic acid.