EZN-2208, a novel poly ethylene glycol-SN38 conjugate, improves pharmacological properties of SN38 in mice and rats.

1496 Background: SN38 (10-hydroxy-7-ethyl-camptothecin) is the active moiety of CPT-11. Due to its poor solubility, SN38 has not been used clinically without extensive formulation effort. We have synthesized a novel polyethylene glycol (PEG)-SN38 conjugate (EZN-2208) by linking SN38 with a 40k 4-arm-PEG, via a glycine linker. EZN-2208 is a water soluble molecule that is highly efficacious in multiple xenograft models when given intravenously and has significantly better therapeutic efficacy compared with CPT-11. Here, we report the pharmacokinetics of EZN-2208 in mice and rats. Methods: Naive (tumor free) ICR mice were administered EZN-2208 via lateral tail vein at dose level of 20 mg/kg (SN38 equivalent). In the rat study, dose levels of 3, 10, and 30 mg/kg (SN38 equivalent) were used. Plasma samples were collected at varied time points from the animals and analyzed for EZN-2208 and released SN38. Results: In both mice and rats, EZN-2208 had a biphasic clearance from the circulation with an elimination half life of 18-22 h in mice and 12-18 h in rats, SN38 released from EZN-2208 had an apparent elimination half life of 18-26 h in mice and 21-22 h in rats. In rats, the maximum plasma concentration (Cmax) and area under the curve (AUC) increased in a dose proportional manner. The apparent half life of released SN38 from EZN-2208 in mice or rats is significantly longer than the reported apparent half life of released SN38 from CPT-11 and the exposure of released SN38 from EZN-2208 is significantly higher than the reported exposure of released SN38 from CPT-11. The clearance of the parent compound was 5.29 mL/hr/kg and 0.35 mL/hr/kg for the mice and rats, respectively. The estimated volume of distribution at steady state (Vss) of the parent compound was 132 mL/kg and 5.49 mL/kg for the mice and rats, respectively. The clearance of the released SN38 was 202 mL/hr/kg for the mice and 131 mL/hr/kg for the rats. The estimated Vss of released SN38 was 3094 mL/kg for the mice and 2384 mL/kg for the rats. Both in mice and rats, enterohepatic circulation of released SN38 was observed. Conclusions: EZN-2208 is a novel water soluble prodrug of SN38 and provides a longer circulation half life and exposure to the parent drug, SN38 in mice and rats. The excellent efficacy of EZN-2208 observed in the xenograft models may be due to its longer circulation half life and exposure. A study designed to investigate if EZN-2208 or SN38 accumulates in the tumors is underway.