Abstract 3599: The plasma and cerebrospinal fluid pharmacokinetics of satraplatin after intravenous administration in non-human primates

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: Satraplatin is an orally bioavailable platinum analog with preclinical activity (IC50 range in tumor cell lines 0.04 - 16 µM) in cisplatin sensitive and resistant models and clinical activity in adults with refractory cancers including prostate cancer. The cerebrospinal fluid (CSF) penetration of cisplatin and carboplatin in non-human primates (NHP) is limited (3.6% and 3.8%, respectively). We evaluated the plasma and CSF pharmacokinetics (PK) of satraplatin, which is more lipophilic than other platinum analogs, after an intravenous (IV) dose in a NHP model. Methods: Satraplatin 120 mg/m2 was administered as 1 h IV infusion in DMSO (5%) and normal saline to 5 NHP. Serial blood and CSF samples were obtained over 48 hours. Plasma was separated immediately and ultrafiltrate (UF) was prepared by centrifugation through a Microcon 10K MWCO filter. CSF was obtained from an indwelling Ommaya reservoir (n=4) or from a temporary lumbar catheter (n=1). Platinum was quantified in the plasma UF and CSF using a validated atomic absorption spectroscopy assay with lower limit of quantification of 0.03 µM in UF and CSF. Pharmacokinetic parameters were estimated using non-compartmental analyses. CSF penetration was calculated from the AUCCSF:AUCPlasma. Results: Satraplatin was well tolerated by all NHP. Pharmacokinetic parameters (median and range) for satraplatin plasma UF were Cmax 8.3 (5.7-10.6) µM, AUC0-48h 28.3 (22.6-33.2) µM·h, AUC0-inf 34.2 (24.7-38.2) µM·h, clearance 3.6 (2.4-4.3) L/h, and t1/2 18.8 (13.4-25) h. Satraplatin was detected in the CSF of all NHP. For the 4 NHP with Ommaya reservoirs PK parameters were: tmax 1.5 (1.3-2.1) h from the start of infusion, Cmax 0.07 (0.02-0.12) µM, AUC0-48h 1.2 (0.49-2.43) µM·h, ratio AUC0-48h CSF:AUC0-48h Plasma was 4.3 (2.2-7.4) %. For the NHP with lumbar catheter and limited CSF samples the tmax was 1.1 h, and Cmax was 0.62 µM. Conclusions: Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3599.