title: Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction: phase I NCI Organ Dysfunction Working Group Study NCI-6432.
abstract: OBJECTIVE
  The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations.
  
  
  METHODS
  Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m(2) standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m(2), respectively, up to a 1.3 mg/m(2) maximum. Serial blood samples were collected for 24 hours postdose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements.
  
  
  RESULTS
  Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC(0-tlast)) or C(max) compared with patients with normal function. Mean dose-normalized AUC(0-tlast) was increased by approximately 60% on day 8 in patients with moderate or severe impairment.
  
  
  CONCLUSIONS
  Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m(2).
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan 48201, USA. lorussop@karmanos.org
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.forename: Daniel
authors.initials: D
authors.lastname: Mulkerin
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Shibata
authors.forename: Anne
authors.initials: A
authors.lastname: Hamilton
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Rachel
authors.initials: R
authors.lastname: Neuwirth
authors.forename: Dixie-Lee
authors.initials: DL
authors.lastname: Esseltine
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D000069286:Bortezomib; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib