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

Abstract

Abstract 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 (IC50 <1 nM), is currently under clinical evaluation for treatment of pediatric malignancies. To evaluate prexasertib in preclinical efficacy studies for pediatric brain tumor models, the ratio of free drug concentrations between the central nervous system (CNS) and plasma (Kpu,u) is typically computed as a surrogate to measure CNS penetration. To facilitate the prospective determination of preclinical CNS Kpu,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 (D'Argenio, 1981) to derive a limited sampling model (LSM) for use in upcoming cerebral microdialysis studies. The results of our plasma PK studies showed a Cmax, 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.