DDEL-17CSF PHARMACOKINETICS AND PHARMACODYNAMICS IN BRAIN CANCER PATIENTS ON HIGH-DOSE ERLOTINIB

Abstract

Failure of brain cancer patients to respond to traditional doses of small molecule inhibitors necessitates a change in the treatment paradigm. We hypothesize that alternate high-dose pulsatile regimens would effectively target brain tumors in such patients. Here, we present the pharmacokinetic and pharmacodynamic effects of high-dose erlotinib in patients with primary glioma or metastatic NSCLC patients. Among the five patients examined, erlotinib concentrations reached up to 131nM in the cerebrospinal fluid (CSF), when high-dose erlotinib was administered at 600 to 1200 mg every four to six days. Additionally, CSF drug clearance was decreased, with an increased dosing regimen in one of the patients. In one patient, the area under the curve (AUC) estimations increased by 24% for the CSF, but only 2% increase for the plasma, following an increase in dose from 150 mg to 600 mg of erlotinib. Importantly, increasing CSF concentrations of erlotinib directly correlated with effects on kinase activity in tumor cells from the CSF. Thus, our data indicate that high-dose pulsatile erlotinib improves its CSF pharmacokinetics; moreover, this regimen is associated with a corresponding pharmacodynamic effect on tumors. Our approach may overcome the blood-brain barrier, and prove transformative for the treatment of patients with primary and metastatic brain cancers.