title: Plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite OSI-420.
abstract: OBJECTIVE
  To report cerebrospinal fluid (CSF) penetration of erlotinib and its metabolite OSI-420.
  
  
  METHODS
  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 approximately 9%, respectively, using both estimate methods. The maximum steady-state CSF concentration of erlotinib was approximately 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.
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. alberto.broniscer@stjude.org
authors.forename: Alberto
authors.initials: A
authors.lastname: Broniscer
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Melinda
authors.initials: M
authors.lastname: O'Shaughnessy
authors.forename: Charles
authors.initials: C
authors.lastname: Fraga
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Krasin
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000188:drug therapy*; D002648:Child; D000069347:Erlotinib Hydrochloride; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D011799:Quinazolines / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; C487471:OSI-420; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride