title: Clinical and pharmacologic study of the farnesyltransferase inhibitor tipifarnib in cancer patients with normal or mildly or moderately impaired hepatic function.
abstract: OBJECTIVE
  This study explored the feasibility of treating patients with impaired hepatic function with tipifarnib. The safety profile, pharmacokinetics, and relationship between the pharmacokinetics and toxicities were evaluated.
  
  
  METHODS
  Patients with mildly or moderately impaired hepatic function (Child-Pugh classification) were treated with tipifarnib bid on days 1 to 5 of cycle 1. Further dosing was based on the individual day 5 pharmacokinetic data and absolute neutrophil count. For patients with normal hepatic function, tipifarnib was dosed on days 1 to 14, followed by 1 week of rest. For all patients, in subsequent cycles, tipifarnib was administered for 21 consecutive days out of every 28 days.
  
  
  RESULTS
  Twenty-eight patients were included in the normal (n = 16), mild (n = 9), and moderate (n = 3) impairment groups. The most important grade 3 to 4 hematologic toxicity was leukocytopenia/neutropenia, which was mostly observed in patients with moderate impairment. Common nonhematologic toxicities were fatigue, nausea, and vomiting. The pharmacokinetic data showed higher plasma concentrations of tipifarnib in patients with liver impairment compared with patients with normal hepatic function.
  
  
  CONCLUSIONS
  In patients with mildly impaired hepatic function, tipifarnib can be administered safely at a starting dose of 200 mg bid, but it is not safe to treat patients with moderate hepatic impairment.
authors.affiliation: Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. wan.les@quicknet.nl
authors.forename: Wandena S
authors.initials: WS
authors.lastname: Siegel-Lakhai
authors.forename: Mirjam
authors.initials: M
authors.lastname: Crul
authors.forename: Peter
authors.initials: P
authors.lastname: De Porre
authors.forename: Steven
authors.initials: S
authors.lastname: Zhang
authors.forename: Ilsung
authors.initials: I
authors.lastname: Chang
authors.forename: Henk
authors.initials: H
authors.lastname: Boot
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy*; D009504:Neutrophils / Q000187:drug effects; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D015363:Quinolones; D051231:Farnesyltranstransferase; C402769:tipifarnib