Brain Distribution Of The Mdm2 Inhibitor, Rg7112: Single Dose Escalation And Repeated Doses Studies.

e13582 Background: MDM2 amplification seen in 14% of glioblastoma (GBM) is a potential therapeutic target. We have shown that RG7112, an oral non-genotoxic MDM2 antagonist, crosses the blood brain barrier and shows in vivo efficacy in GBM mouse models (repeated dose 100 mg/kg QD). The present work investigated the Brain distribution of RG7112 to optimize the scheme delivery toward increased efficacy. Methods: To investigate Brain distribution, single dose escalation (SDE) and repeated doses (RD) studies were conducted. For both studies : (i) RG7112 was delivered to healthy Swiss mice, (ii) RG7112 Plasma and Brain concentrations were quantified using LC-MS/MS method. The AUC0-t were calculated using the trapezoidal rule and compared using Bailer method. Correlations were assessed using the Pearson product-moment method. SDE study enrolled 21 mice to test 3 doses of RG7112 (10, 100, and 200 mg/kg once) at 7 time-points (0, 1, 2, 4, 8, 16, and 24 hours after treatment). RD study enrolled 21 mice to test 100 ...