EXTH-25. THE CSF PENETRATION OF THE PROCASPASE-ACTIVATING COMPOUND (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE (TMZ) IN A NONHUMAN PRIMATE CSF ACCESS MODEL

Abstract

Abstract BACKGROUND The synergistic activity of temozolomide (TMZ) administered in combination with procaspase-activating compound (PAC-1) has been reported in pre-clinical mouse models and canine patients, leading to clinical trials in adults with glioblastoma. To optimize pediatric clinical trial design, a translational pharmacokinetic CSF penetration study was conducted using a pre-clinical nonhuman primate non-tumor bearing CSF access model with TMZ and PAC-1 administered alone and in combination. METHODS Four male rhesus macaques with CSF lateral ventricular reservoirs received PAC-1, 15 mg/kg orally [Human Equivalent Dose (HED) 558 mg/m2/day] or TMZ, 1-hr IV infusion, 7.5 mg/kg (HED 150 mg/m2) as single and combination agent administration. Paired plasma and CSF samples were collected for 0–96 hours. PAC-1 and TMZ were quantified by LC-MS/MS. Pharmacokinetic parameters were calculated using noncompartmental methods. Statistics were determined via Mann-Whitney test. RESULTS (Mean ± Standard Deviation): For TMZ: Plasma AUC0-24 (hr*ng/ml) single agent (n=4): 28590 ± 4888 and in combination (n=4): 32736 ± 10147. CSF AUC0-24 (hr*ng/ml) single agent (n=4):14406 ± 1279 and in combination (n=4):15614 ± 1767. CSF penetration (% AUCCSF: AUCPLASMA) single agent: 50.9% ± 2.2 and in combination:49.6% ± 8.4. For PAC-1: Plasma PAC-1 AUC0-24 (hr*ng/ml) single agent (n=4): 2556 ± 2157 and in combination (n=4): 1947 ± 1311. CSF PAC-1 AUC0-24 (hr*ng/ml) single agent (n=2): 8.7 ± 1.1 and in combination (n=3):12.9 ± 10.2. CSF penetration single agent: 0.2% ± 0.03 and in combination: 0.4% ± 0.38. CSF PAC-1 tlag and Tmax pharmacokinetic parameters decreased with concurrent TMZ administration. CONCLUSIONS In this non-tumor bearing pre-clinical nonhuman primate model the CSF penetration of PAC-1 was low and not notably affected by the concurrent administration of TMZ. TMZ CSF penetration for single administration was within previously reported ranges and also appeared unaffected when administered in combination with PAC-1.