Plasma and Cerebrospinal Fluid Pharmacokinetics of Erlotinib and Its Active Metabolite OSI-420

Purpose: To report cerebrospinal fluid (CSF) penetration of erlotinib and its metabolite OSI-420. Experimental Design: Pharmacokinetic measurements were done in plasma (days 1, 2, 3, and 8 of therapy) and, concurrently, in plasma and CSF (before and at 1, 2, 4, 8, and 24 h after dose on day 34 of therapy) in an 8-year-old patient diagnosed with glioblastoma who received local irradiation and oral erlotinib in a phase I protocol. CSF samples were collected from a ventriculoperitoneal shunt, which was externalized because of infection. Erlotinib concentrations were determined by liquid chromatography/mass spectrometry. CSF penetration of erlotinib and OSI-420 were estimated by a compartmental model and by calculating the ratio of CSF to plasma 24-h area under concentration-time curve (AUC 0-24 ). Results: This patient was assigned to receive erlotinib at a dose level of 70 mg/m 2 , but the actual daily dose was 75 mg (78 mg/m 2 ). Erlotinib and OSI-420 plasma pharmacokinetic variables on days 8 and 34 overlapped to suggest that steady state had been reached. Whereas erlotinib and OSI-420 AUC 0-24 in plasma on day 34 were 30,365 and 2,527 ng h/mL, respectively, the correspondent AUC 0-24 in the CSF were 2,129 and 240 ng h/mL, respectively. Erlotinib and OSI-420 CSF penetration were 7% and ∼9%, respectively, using both estimate methods. The maximum steady-state CSF concentration of erlotinib was ∼130 ng/mL (325 nmol/L). Conclusions: The plasma pharmacokinetics of erlotinib in this child overlapped with results described in adults. Oral administration of erlotinib achieves CSF concentrations comparable with those active against several cancer cell lines in preclinical models.