Evaluation Of Brain Pharmacokinetics As A Potential Differentiation Factor For The Mek Inhibitors, Msc2015103 And Pimasertib

MSC2015103 is an orally bio-available, selective, and highly potent small molecule inhibitor of MEK1/2. As a follower to the front-runner MEK inhibitor, pimasertib (MSC1936369/AS703026), a prime objective for the program is to differentiate the two compounds. Results from previous pharmacokinetic (PK) studies of MSC2015103 and pimasertib in mice had shown that both compounds could effectively cross the blood-brain barrier, but that MSC2015103 was retained in the brain longer than pimasertib. This was further confirmed in a study examining the whole-body distribution of radio-labeled compounds in mice. It is unclear whether the differential brain PK characteristics of the two agents will be clinically significant. To begin to address this, a series of pre-clinical studies were performed. Exposure levels and concurrent target modulation in normal murine brain tissue were examined over time following administration of multiple doses of MSC2015103 and pimasertib. Notable differences in the magnitude and temporal dynamics of exposure were observed; while concentrations of pimasertib in the brain peaked ∼1 hour post-administration (with a correlative decrease in phospho-ERK of ∼90%) with a relatively rapid clearance out of the tissue, concentrations of MSC2015103 increased in the brain over time and remained relatively elevated until 24 hours post-administration (the last time point) with only marginal target modulation observed. As more dramatic inhibition of pERK has previously been observed in subcutaneous tumors in mice in the presence of the same exposure of MSC2015103, murine brain orthotopic models of glioblastoma were employed to compare the relative target modulation of MSC2015103 and pimasertib in tumor tissue within the brain compartment, as well as their potential anti-tumor effects. Data from these orthotopic studies demonstrated similar high levels of phospho-ERK inhibition for both MSC2015103 and pimasertib in glioblastoma tumor tissue, which correlated with similar anti-tumor activity in the U87 model. The PK of MSC2015103 varied considerably from pimasertib, with a higher exposure (AUC1-24h) ratio of brain tumor-to-normal brain with MSC2015103 as compared with pimasertib. In line with the PK findings, MSC2015103 inhibited phospho-ERK in brain tumors but with relatively less target modulation in normal brain tissue, whereas pimasertib showed similar inhibition of phospho-ERK in both tissues. Collectively, these findings suggest a potential improvement in the safety/therapeutic index in the brain for MSC2015103. This may translate into other tissues, such as the eye, which has a similar blood barrier, and may be important in light of ocular toxicities observed in clinical trials with other MEK inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-456. doi:1538-7445.AM2012-LB-456