Slow-release conjugates of SN-38
Conjugates of SN-38 that provide optimal drug release rates and minimize the formation of the corresponding glucuronate are described. The conjugates release SN-38 from a polyethylene glycol through a β-elimination mechanism.
1. A method of providing continuous, low-dose exposure to SN-38 to a patient in need of such exposure, said method comprising administering to the patient a conjugate of formula II or a pharmaceutical formulation thereof
wherein m=1-6 and n is 200-250;
or pharmaceutical composition thereof.
2. The method of claim 1 , wherein the concentration of free SN-38 is maintained between 15 and 5 nM between once-weekly administrations.
3. The method of claim 1 wherein the C max /C min observed between administrations is less than or equal to 10 between once-weekly administrations.
4. The method of claim 3 wherein the C max /C min observed between administrations is less than or equal to 5 between once-weekly administrations.
5. A method to control the level of SN-38 glucuronide (SN-38G) in the plasma of a patient requiring treatment with SN-38, said method comprising administering a conjugate of formula II or a pharmaceutical formulation thereof
wherein m=1-6 and n is 200-250;
or pharmaceutical composition thereof;
to said patient, wherein the resulting SN-38G/SN-38 ratio is less than 0.2.
6. The method of claim 1 , wherein the pH of the formulation is between 4.0 and 6.0.
7. The method of claim 5 , wherein the pH of the formulation is between 4.0 and 6.0.
8. The method of claim 1 , wherein in said conjugate m is 1 and n is approximately 225.
9. The method of claim 5 , wherein in said conjugate m is 1 and n is approximately 225.