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- W2591248049 abstract "e13080 Background: MPC-6827 is a small molecule microtubule disrupting agent that is being evaluated in phase II studies for the treatment of glioblastoma multiforme. It crosses the blood-brain barrier and achieves brain to plasma concentration ratios of up to 30 in animal models. MPC-6827 is active in multiple xenograft models when dosed on a weekly schedule. Here we explore its activity when dosed on a daily schedule or continuously for 24 hours. Methods: B16 mouse melanoma or OVCAR3 human ovarian cancer cells were implanted subcutaneously into athymic mice (nu/nu) for xenograft studies. MPC-6827 was dosed intravenously (IV) at its maximal tolerated dose of 7.5 mg/kg once or daily at 1 mg/kg for five days for the B16 study. For the OVCAR-3 study, MPC-6827 was dosed at 5 mg/kg once IV or at 2.5-, 5- or 10 mg/kg/day intraperitoneally (IP) with an Alzet mini-pump for one day. Results: In the B16 model, MPC-6827 dosed at 7.5 mg/kg resulted in 72% tumor growth inhibition (TGI) on Day 7 relative to vehicle (p=0.01), whereas 1 mg/kg daily dosing for five days resulted in only 22% TGI (p=0.68). In the OVCAR-3 model, MPC-6827 delivered IP at 2.5 mg/kg over a period of 24 h resulted in no inhibition of xenograft growth relative to vehicle on Day 17. In contrast, the single 5 mg/kg IV dose resulted in 50% regression. The median time to tumor volume >1,500 mm3 was 31 days for the vehicle group, 28.5 days for the 2.5 mg/kg/day IP group and >39 days (p=0.04) for the 5 mg/kg IV group. Plasma concentration of MPC-6827 was 35 ng/mL at 24 h when delivered IP at 2.5 mg/kg/day, whereas Cmax was 1291- and 105 ng/mL with a 5- and 1 mg/kg IV dose, respectively. The AUC for the 5- and 1 mg/kg doses were 657- and 79 hr*ng/mL, respectively. Conclusions: MPC-6827 shows significant activity in animal models when dosed intermittently at 5 mg/kg or higher. Anti-xenograft activity is not observed when the single dose is divided into proportionately smaller daily doses or when the compound is dosed continuously for 24 hours. Thus the optimal dosing regimen for MPC-6827 in xenograft models is intermittent high doses, which result in transiently elevated plasma concentrations of the compound." @default.
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- W2591248049 date "2011-05-20" @default.
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- W2591248049 title "Comparison of MPC-6827 activity in xenograft models with different dosing schedules." @default.
- W2591248049 doi "https://doi.org/10.1200/jco.2011.29.15_suppl.e13080" @default.
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