EXTH-65. PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS COMPARISON OF BRAF AND MEK INHIBITORS FOLLOWING SINGLE AND EXTENDED ADMINISTRATION IN A PRE-CLINICAL NON-HUMAN PRIMATE MODEL

Abstract BACKGROUND Aberrations in the MAPK signaling pathway are present in adult and pediatric CNS tumors. The BRAF and MEK inhibitors Dabrafenib, Vemurafenib, Selumetinib and Trametinib, alone or in combination, have demonstrated clinical efficacy. However, minimal CSF penetration has been demonstrated in pre-clinical models with single dose administration. CSF penetration of these agents was compared following single and extended oral administration in a nonhuman CSF Lateral Reservoir model to determine if CSF penetration increases at steady state. METHODS Agents were administered orally, to each subject (n=9), in single or multiple doses, as serial single agent studies, with washout periods between studies. The following dosages (Human equivalent dose HED) were utilized in the studies: Single Dosage-Selumetinib 2.5 mg/kg (50.0 mg/m2), Dabrafenib 8.0 mg/kg (160 mg/m2), Vemurafenib 26 mg/kg (520 mg/m2), Trametinib 0.06 and 0.12 mg/kg (1.2 and 2.4 mg/m2). Extended dosages-Selumetinib 2.5 mg/kg BID x 3 days (50.0 mg/m2), Dabrafenib 4.0 mg/kg BID x 2 days (160 mg/m2/day), Vemurafenib 26 mg/kg BID x 3 days (520 mg/m2), Trametinib 0.05 mg/kg x 10 days BID (1.0mg/m2). Paired serial plasma and CSF samples were collected. Agents were quantified by uHPLC-MS/MS. Pharmacokinetic parameters were calculated via noncompartmental methods. Plasma exposure reported as Area Under the Curve (AUC) and CSF penetration as ratio of CSF:plasma AUC. Statistical significance determined by t-test. RESULTS Single administration AUCinf/D (hr*ng/ml/mg) vs. extended administration AUCtau/D (hr*ng/ml/mg) for each agent: Vemurafenib-Plasma 30.9–351.4 vs.29.2–379.7, CSF-non-quantifiable; Dabrafenib-Plasma 29.3–102.6 vs.3.4–58.2, CSF-0.12–0.54 vs 0.04–0.19, % CSF:Plasma-0.3–0.84 vs.0.32–1.3; Trametinib-Plasma AUC indeterminable, CSF-non-quantifiable; Selumetinib-Plasma 69.8–133.0 vs.26.5–81.2; CSF-AUC indeterminable vs. 0.37–0.86, % CSF:Plasma-Indeterminable vs. 0.78–1.4. T-test: A downward trend in Dabrafenib and Selumetinib plasma AUC and a marked upward trend in Selumetinib CSF AUC. CONCLUSIONS With the exception of Selumetinib, the CSF exposure of BRAF and MEK inhibitors studied did not markedly increase following extended dosing.