PII-156 - STRAIN- AND ROUTE-DEPENDENT PLASMA PHARMACOKINETICS AND BRAIN PENETRATION OF PACLITAXEL.

T. Drabison¹, Y. Xu², E. Ahmed¹, S. Kandalai¹, K. Hoyt¹, K. Obrietan¹, S. Hu¹, A. Sparreboom¹, L. Pyter¹, E. Eisenmann¹; ¹The Ohio State University, ²The Ohio State Univerity, OH, USA.

Background: Paclitaxel, an antineoplastic agent, is highly effective in treating cancers but limited by the development of adverse events, including paclitaxel-induced CNS toxicities. The findings from utilizing these preclinical models are only useful if they are translationally relevant. The potential impact of route-, formulation-, and/or strain-dependent pharmacokinetic (PK) and organ-accumulation differences has largely been ignored. We hypothesize that paclitaxel PK is strain- and route-dependent and that this results in variable toxicity phenotypes.

Methods: PK studies were performed to characterize paclitaxel PK. We administered 10 mg/kg paclitaxel to seven strains of mice (C57BL/6NTac, 129S6/SvEvTac, FVB, NSG, BALBc, CD2F1, and DBA) either IP or IV. Strains were selected based on their use in preclinical models, existing bioavailability data, or both. Concentrations of paclitaxel in plasma and brain were determined by a validated LC-MS/MS method and analyzed using Phoenix WinNonlin. In vitro and ex vivo methods were used to determine whether paclitaxel is directly toxic to neurons.

Results: Paclitaxel PK parameters differed significantly between strain and route. Between-strain differences in AUC varied up to 1.7-fold for IV dosing and 2.0-fold for IP dosing. IP bioavailability varied up to 1.9-fold between strains. Brain accumulation of paclitaxel was also strain- (P < 0.05) and route-dependent (P < 0.01) with up to a 3.4-fold difference in brain accumulation when administered IV and up to a 1.9-fold difference when administered IP. Ex vivo experiments demonstrated a concentration-dependent decrease in neuronal viability with paclitaxel treatment, which was more pronounced in the presence of verapamil.

Conclusion: We found that both paclitaxel PK and brain penetration are strain- and route-dependent and that paclitaxel exhibits concentration-dependent cytotoxicity to primary neurons at achievable concentrations. Altogether, these observations provide the rationale to further investigate (i) if strain- and route-dependent paclitaxel PK variation are related to variation in toxicity phenotypes, (ii) if paclitaxel toxicities are a direct effect of cellular accumulation, and (iii) if paclitaxel toxicities are dependent on accumulation in specific cell types.