title: Increased bioavailability of intravenous versus oral CI-1033, a pan erbB tyrosine kinase inhibitor: results of a phase I pharmacokinetic study.
abstract: OBJECTIVE
  In phase I studies with oral CI-1033, dose-limiting toxicities were primarily gastrointestinal, supporting the exploration of i.v. dosing to achieve optimal drug exposures by increasing bioavailability.
  
  
  METHODS
  Fifty-three patients with advanced nonhematologic malignancies received i.v. CI-1033 via 30-minute infusions (10-500 mg) on a thrice-weekly schedule. Pharmacokinetic samples were collected on days 1 and 8 and evaluated using noncompartmental analysis.
  
  
  RESULTS
  Dose levels evaluated were 10, 20, 30, 45, 67.5, 100, 150, 225, 337.5, and 500 mg. The maximum administered dose was 500 mg, whereas the maximum tolerated dose was 225 mg. The most common treatment-related grade 1 to 2 adverse events were rashes (38% of patients), nausea (17%), vomiting (17%), stomatitis (14%), and diarrhea (13%). Most common grade 3 adverse events were hypersensitivity reactions (7.5%), rashes (3.8%), and diarrhea (3.8%). No grade 4 toxicities were observed. Ten of the 53 (19%) patients had disease stabilization at their first efficacy evaluation visit (including two with minor responses). A 5- to 10-fold increase in i.v. C(max) was noted with a 3-fold increase in AUC compared with oral CI-1033 at equivalent doses. Treatment-related gastrointestinal adverse events were notably less frequent with this i.v. regimen.
  
  
  CONCLUSIONS
  CI-1033 was safely given i.v. up to 225 mg/dose on a thrice-weekly schedule, with evidence of antitumor activity. At equivalent doses, the bioavailability of i.v. CI-1033 is thrice that of the oral formulation. Treatment with i.v. CI-1033 is feasible and may be warranted when increased drug exposures are desired.
authors.affiliation: Division of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. simongr@moffitt.usf.edu
authors.forename: George R
authors.initials: GR
authors.lastname: Simon
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Garrett
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Olson
authors.forename: Michael
authors.initials: M
authors.lastname: Langevin
authors.forename: Irene A
authors.initials: IA
authors.lastname: Eiseman
authors.forename: John J
authors.initials: JJ
authors.lastname: Mahany
authors.forename: Charles C
authors.initials: CC
authors.lastname: Williams
authors.forename: Richard
authors.initials: R
authors.lastname: Lush
authors.forename: Adil
authors.initials: A
authors.lastname: Daud
authors.forename: Pamela
authors.initials: P
authors.lastname: Munster
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiappori
authors.forename: Mayer
authors.initials: M
authors.lastname: Fishman
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Peter F
authors.initials: PF
authors.lastname: Lenehan
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D009369:Neoplasms / Q000188:drug therapy*; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C420268:Canertinib