title: Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study.
abstract: OBJECTIVE
  To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population.
  
  
  METHODS
  Sixty-two adult cancer patients received intravenous bortezomib at 0.7-1.5 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73 m(2) into five cohorts: normal renal function (≥ 60 ml/min/1.73 m(2)); mild dysfunction (40-59 ml/min/1.73 m(2)); moderate dysfunction (20-39 ml/min/1.73 m(2)); severe dysfunction (<20 ml/min/1.73 m(2)); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed.
  
  
  RESULTS
  Bortezomib escalation to the standard 1.3 mg/m(2) dose was well tolerated in all patients with CrCl ≥ 20 ml/min/1.73 m(2); 0.7 mg/m(2) was tolerated in three patients with severe renal dysfunction (<20 ml/min/1.73 m(2)). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m(2) in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function.
  
  
  CONCLUSIONS
  Bortezomib 1.3 mg/m(2) is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.
authors.affiliation: University of Wisconsin Carbone Cancer Center, 600 Highland Ave, Madison, WI 53792, USA.
authors.forename: Ticiana B
authors.initials: TB
authors.lastname: Leal
authors.forename: Scot C
authors.initials: SC
authors.lastname: Remick
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Angela
authors.initials: A
authors.lastname: Davies
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Anne
authors.initials: A
authors.lastname: Hamilton
authors.forename: Patricia A
authors.initials: PA
authors.lastname: LoRusso
authors.forename: Stephen
authors.initials: S
authors.lastname: Shibata
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: James
authors.initials: J
authors.lastname: Mier
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.forename: Rachel
authors.initials: R
authors.lastname: Neuwirth
authors.forename: Lisa
authors.initials: L
authors.lastname: von Moltke
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: Daniel
authors.initials: D
authors.lastname: Mulkerin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001897:Boronic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000069286:Bortezomib; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D011719:Pyrazines / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003404:Creatinine