Antitumor efficacy and pharmacokinetics of a novel gemcitabine oral formulation (INNO-D07001) in xenograft animal models.

Abstract

e14699 Background: INNO-D07001 is a novel oral gemcitabine formulation which was developed to enhance the oral bioavailability of gemcitabine and it has been successfully demonstrated in both beagle dogs as well as nude mice. The objectives of this study were to examine the antitumor activity of this novel gemcitabine oral formulation in human xenograft models of pancreatic tumors with different daily doses as well as various dosing schedules. Methods: The INNO-D07001 dosing solutions (gemcitabine oral formulation) were formulated freshly before treatment and water for injection (USP) was used as the diluent. There were seven groups in the study and it was ten female NCr-nu/nu mice (with human CFPAC-1 pancreatic tumor) per group. Two doses (5 mg/kg and 10 mg/kg) and three dosing schedules (Q1D, Q2D, and Q3D) were examined. Water for injection (by oral administration) was used as the blank control and Gemzar (180 mg/kg by I.V.) was used as the active control. All INNO-D07001 dosing solutions were administered to mice by P.O. and, on the other hand, Gemzar was administered to mice by I.V. All animals were designed to receive doses for 12 days based on different doses and dosing schedules. Total body weights and tumor sizes were recorded continuously for evaluating the toxicity and antitumor activity, respectively, of INNO-D07001. Results: Oral administration of INNO-D07001 once daily at doses of 10 and 5 mg/kg/dose was not tolerated. In contrast, oral administration of INNO-D07001 on a Q2Dx6 schedule at a dose of 10 mg/kg/dose and on a Q3Dx4 schedule at doses of 10 and 5 mg/kg/dose was well tolerated. Moreover, the INNO-D07001 treatment at a dose of 10 mg/kg/dose on a Q2Dx6 schedule produced statistically significant inhibition of tumor growth (i.e. more than 60% inhibition rate comparing to the blank control) on the last treatment day. Conclusions: The novel gemcitabine oral formulation (INNO-D07001) is well tolerated and effective at a dose of 10 mg/kg/dose on a Q2Dx6 schedule to show the significant inhibition of pancreatic tumor growth. Future preclinical study in toxicity evaluation with repeating doses is ongoing in order to provide adequate safety information before entering phase I clinical study.