Abstract 4927: Plasma and CNS pharmacokinetics of the CHK-1 inhibitor prexasertib (LY-2606368) in mice bearing orthotopic group 3 medulloblastoma

Many children with brain tumors have limited treatment options and poor long-term survival. A key protein kinase involved in activating and maintaining the S and G2/M checkpoints is CHK1, which when inhibited in the absence of p53 leads to loss of DNA damage checkpoints and can enhance the activity of many DNA-damaging agents. Prexasertib (LY-2606368), a potent and selective small molecule inhibitor of CHK1 protein kinase activity in vitro (IC 50 u,u ) is typically computed as a surrogate to measure CNS penetration. To facilitate the prospective determination of preclinical CNS Kp u,u values, we evaluated the plasma pharmacokinetic (PK) disposition of prexasertib in a murine model of medulloblastoma. A plasma PK study was performed using CD1 nude mice orthotopically implanted with group 3 medulloblastoma to obtain initial prexasertib PK parameters. Tumor growth was assessed by bioluminescence imaging (D-Luciferin) and mice were enrolled in the study once tumors reached 1x10 ~8-9 photons/second. Prexasertib mesylate monohydrate was reconstituted in 20% Captisol and administered subcutaneously at a dosage of 10 mg/kg (free base). A population based study design was used in which 3 samples per mouse were obtained. Plasma samples were prepared using a liquid-liquid extraction technique, and analyzed for prexasertib using a validated LC-MS/MS method (LLOQ = 0.2 µg/L). A two-compartment PK model was fit to the prexasertib concentration-time data using nonlinear mixed effects modeling (NONMEM 7.3, ICON Development Solutions). Plasma PK parameters from this model were used with the D-optimality criterion as implemented in ADAPT (D9Argenio, 1981) to derive a limited sampling model (LSM) for use in upcoming cerebral microdialysis studies. The results of our plasma PK studies showed a C max , terminal half-life, and AUC in CD1 nude mice bearing group 3 medulloblastoma of 1015 µg/L, 4.5 hours, and 1773 µg*hr/L, respectively. The LSM for plasma PK that will be used in the cerebral microdialysis studies include the time points of 0.25, 6.6, and 24 hours. Now that the plasma PK and a LSM are defined, we are poised to begin cerebral microdialysis studies in CD1 nude mice bearing group 3 medulloblastoma. Citation Format: Anil Maharaj, Abigail Davis, Bo Zhong, Martine F. Roussel, Clinton F. Stewart. Plasma and CNS pharmacokinetics of the CHK-1 inhibitor prexasertib (LY-2606368) in mice bearing orthotopic group 3 medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4927.