title: Phase I pharmacokinetic and pharmacodynamic study of weekly 1-hour and 24-hour infusion BMS-214662, a farnesyltransferase inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  BMS-214662 is a potent, nonpeptide, small molecule inhibitor of human farnesyltransferase (FT). We have conducted a phase I pharmacokinetic (PK) and pharmacodynamic study of BMS-214662 administered intravenously weekly with 1- and 24-hour infusions. The objectives were to determine the dose-limiting toxicities and the recommended dose (RD), to describe PKs, and to evaluate the relationships between BMS-214662 exposure, FT inhibition, downstream signaling, and induction of apoptosis in tumor samples.
  
  
  METHODS
  Patients with advanced solid tumors and adequate organ function were eligible. The dose was escalated according to a modified Fibonacci schedule.
  
  
  RESULTS
  high (> 80%) but short-lived (< or = 6 hours) in the 1-hour infusion and moderate (> 40%) but long-lived (24 hours) in the 24-hour infusion. BMS-214662 induced apoptosis in tumors but did not inhibit MAPK signaling.
  
  
  CONCLUSIONS
  BMS-214662 can be safely delivered in both the 1-hour and 24-hour infusions at biologically active doses, with the preclinical, PK, and pharmacodynamic profiles favoring the 24-hour schedule.
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. jtabernero@vhebron.net [corrected]
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Fredy
authors.initials: F
authors.lastname: Rojo
authors.forename: Irene
authors.initials: I
authors.lastname: Marimón
authors.forename: Maurizio
authors.initials: M
authors.lastname: Voi
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.forename: Marta
authors.initials: M
authors.lastname: Guix
authors.forename: Federico
authors.initials: F
authors.lastname: Vázquez
authors.forename: Joan
authors.initials: J
authors.lastname: Carulla
authors.forename: Michael
authors.initials: M
authors.lastname: Cooper
authors.forename: Jordi
authors.initials: J
authors.lastname: Andreu
authors.forename: Anne
authors.initials: A
authors.lastname: Van Vreckem
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.forename: Veeraswamy
authors.initials: V
authors.lastname: Manne
authors.forename: James A
authors.initials: JA
authors.lastname: Manning
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Felip
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Del Campo
authors.forename: Mónica
authors.initials: M
authors.lastname: García
authors.forename: Sonia
authors.initials: S
authors.lastname: Valverde
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D051231:Farnesyltranstransferase; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction
chemical_list: D007093:Imidazoles; D001569:Benzodiazepines; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine