PRECLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC EVALUATION OF NEW ANTICANCER AGENTS FOR BRAIN TUMOR CHEMOTHERAPY

Abstract

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults for which overall prognosis remains poor despite recent treatment advances, thus emphasizing the need for developing effective therapeutic agents. Styryl sulfones belong to a class of non-ATP competitive antineoplastic agents in early stage clinical trials. Detailed investigation of the pharmacokinetics (PKs) and pharmacodynamics (PDs) of novel agents in the preclinical stage plays a pivotal role in drug development that could be applied to guide clinical trials. The main goal of the project was to undertake comprehensive PK and PD evaluation of new agents for brain tumor therapy and in the process establish a PK/PD strategy for the development of such novel agents. The current project was aimed to evaluate the potential of a styryl benzyl sulfone compound, ON01910.Na, as a chemotherapeutic agent for the treatment of GBMs using PK/PD approaches. First, the systemic pharmacokinetics of ON01910 was characterized following single dose intravascular administration of ON01910.Na in healthy mice over a 50-fold dose range of 5 mg/kg - 250 mg/kg. Secondly, an evaluation of the brain and brain tumor disposition of ON01910 was conducted in an orthotopic U87 glioma model in mice using a steady-state dosing regimen, and, in addition, using the same brain tumor model its pharmacodynamic and antiangiogenic activity were determined following multiple dosing. ON01910 exhibited nonlinear pharmacokinetics in the dose range of 50 mg/kg - 250 mg/kg. It showed inadequate brain and brain tumor penetration and insignificant antiangiogenic and antiproliferative activity. The limited brain tumor penetration and activity of ON01910 in the intracerebral glioma model led to the evaluation of ON013105, a prodrug of its more lipophilic anticancer congener, ON013100. A similar PK/PD approach as for ON01910.Na was applied wherein systemic pharmacokinetic properties of ON013105 and its active form, ON013100 in healthy mice, as well as an analysis of their brain and brain tumor distribution following steady-state dosing regimen were determined following administration of prodrug. The active form, ON013100 showed appreciable brain and brain tumor penetration while the prodrug did not. Subsequent pharmacodynamic investigations conducted in vitro identified phosphorylated-ERK (pERK) as a PD marker. To assess time-dependent PK/PD characteristics, mice bearing intracerebral U87 glioma were administered ON013105 at 100 mg/kg intravenously and plasma, brain and brain tumor concentrations of ON013105 and its active form, ON013100 were quantitated as well as tumoral pERK levels. Further, a PK-PD model was developed that characterized plasma, brain and brain tumor concentration-time profiles of ON013105 and ON013100 and tumoral pERK levels. In summary, a PK/PD-driven approach was applied to evaluate and select novel compounds that may have potential in the treatment of brain tumors. The progression of studies yielded one compound, ON013100 that possessed favorable brain tumor distribution and showed PD activity that warrant continued evaluation.