title: Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs (EIAEDs). This study compares the pharmacokinetics and pharmacodynamics of tipifarnib at MTD in patients on and off EIAEDs.
  
  
  METHODS
  Recurrent malignant glioma patients were treated with tipifarnib using an interpatient dose-escalation scheme. Pharmacokinetics and pharmacodynamics were assessed.
  
  
  RESULTS
  Twenty-three assessable patients taking EIAEDs received tipifarnib in escalating doses from 300 to 700 mg bid for 21 of 28 days. The dose-limiting toxicity was rash, and the MTD was 600 mg bid. There were significant differences in pharmacokinetic parameters at 300 mg bid between patients on and not on EIAEDs. When patients on EIAEDs and not on EIAEDs were treated at MTD (600 and 300 mg bid, respectively), the area under the plasma concentration-time curve (AUC)(0-12 hours) was approximately two-fold lower in patients on EIAEDs. Farnesyltransferase inhibition was noted at all tipifarnib dose levels, as measured in peripheral-blood mononuclear cells (PBMC).
  
  
  CONCLUSIONS
  Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs. EIAEDs significantly decreased the maximum concentration, AUC(0-12 hours), and predose trough concentrations of tipifarnib. Even in the presence of EIAEDs, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs. The relevance of these important findings to clinical activity will be determined in ongoing studies with larger numbers of patients.
authors.affiliation: Henry E. Singleton Brain Cancer Research Program, University of California, Los Angeles, CA, USA. tcloughe@ucla.edu
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: John
authors.initials: J
authors.lastname: Kuhn
authors.forename: H Ian
authors.initials: HI
authors.lastname: Robins
authors.forename: Lauren
authors.initials: L
authors.lastname: Abrey
authors.forename: Patrick
authors.initials: P
authors.lastname: Wen
authors.forename: Karen
authors.initials: K
authors.lastname: Fink
authors.forename: Frank S
authors.initials: FS
authors.lastname: Lieberman
authors.forename: Minesh
authors.initials: M
authors.lastname: Mehta
authors.forename: Susan
authors.initials: S
authors.lastname: Chang
authors.forename: Alfred
authors.initials: A
authors.lastname: Yung
authors.forename: Lisa
authors.initials: L
authors.lastname: DeAngelis
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: Larry
authors.initials: L
authors.lastname: Junck
authors.forename: Morris
authors.initials: M
authors.lastname: Groves
authors.forename: Steve
authors.initials: S
authors.lastname: Paquette
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: Kathleen
authors.initials: K
authors.lastname: Lamborn
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Michael
authors.initials: M
authors.lastname: Prados
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D015363:Quinolones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018570:Risk Assessment; D016879:Salvage Therapy; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D015363:Quinolones; C402769:tipifarnib