Clinical pharmacokinetics of erlotinib (E) in glioblastoma multiforme (GBM) patients and its implication for dosing

Abstract

2010 Background: E is an orally active, highly potent and selective inhibitor of the epidermal growth factor receptor (EGFR). Preliminary results from both Phase I and Phase II trials of E in GBM patients have been reported (ASCO 2003, Abs#394 and ASCO 2004, Abs#1555). The purpose of this analysis is to characterize E PK in this patient population when administered with or without CYP3A4 enzyme inducing anti-epileptic drugs (EIAEDs) and to identify a dose to provide equivalent exposure during concomitant therapy in GBM patients. Methods: Intensive PK data were collected in the Phase I study and plasma trough concentration data were collected in the Phase II study at steady-state. A total of 775 E concentrations from 107 patients were available for the analysis. A population PK approach (NONMEM) was used to characterize the clinical PK in this patient population and the effect of EIAEDs on the PK of E. Results: Co-administration of EIAEDs was shown to increase the E clearance (CL/F) by 230% in GBM patients. This effect is similar to that seen in a previous drug-drug interaction study with a CYP3A4 enzyme inducer (rifampicin) in healthy volunteers. For patients with no EIAEDs, population estimates and the %CV of inter-individual variance for CL/F and Vc/F of erlotinib were 5.63 L/hr (44%) and 388 L (40%), respectively. Conclusions: Based on the modeling results, for GBM patients with EIAEDs, an estimate of erlotinib dose of 500 mg/d is needed to achieve an equivalent exposure as patients who receive the dose of 150 mg/d with no EIAEDs. The new population PK model provides an operational tool to predict E exposure during treatment, and simulate alternative dosing regimens for GBM patients. [Table: see text]