title: Pharmacokinetics and excretion of 14C-bendamustine in patients with relapsed or refractory malignancy.
abstract: BACKGROUND
  Bendamustine is an alkylating agent with clinical activity against a variety of hematologic malignancies and solid tumors. To assess the roles of renal and hepatic drug elimination pathways in the excretion and metabolism of bendamustine, a mass balance study was performed in patients with relapsed or refractory malignancies.
  
  
  METHODS
  A single 60-minute intravenous dose of 120 mg/m(2), 80-95 μCi (14)C-bendamustine hydrochloride was administered to six patients, followed by collection of blood, urine, and fecal samples at specified time points up to day 8 or until the radioactivity of the 24-hour urine and fecal collections was below 1% of the administered dose (whichever was longer). Total radioactivity (TRA) was measured in all samples, and concentrations of unchanged bendamustine and its metabolites γ-hydroxy-bendamustine (M3), N-desmethyl-bendamustine (M4), and dihydroxy bendamustine (HP2) were determined in plasma and urine, using validated liquid chromatography-tandem mass spectrometry methods.
  
  
  RESULTS
  The mean recovery of TRA in excreta was 76% of the radiochemical dose. Approximately half of the administered dose was recovered in urine and a quarter in feces. Less than 5% of the administered dose was recovered in urine as unchanged bendamustine. Bendamustine clearance from plasma was rapid, with a half-life of ~40 minutes. Plasma concentrations of M3, M4, and HP2 were very low relative to bendamustine concentrations. Plasma levels of TRA were higher and more sustained as compared with plasma concentrations of bendamustine, M3, M4, and HP2, suggesting the presence of one or more longer-lived (14)C-bendamustine-derived compounds. Fatigue (50%) and vomiting (50%) were the most frequent treatment-related adverse events. A grade 3/4 absolute lymphocyte count decrease occurred in all patients at some point during the study.
  
  
  CONCLUSIONS
  Bendamustine is extensively metabolized, with subsequent excretion in both urine and feces. Accumulation of bendamustine is not anticipated in cancer patients with renal or hepatic impairment, because of the dose administration schedule and short half-life.
authors: Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Anne-Charlotte
authors: AC
authors: Dubbelman
authors: Hilde
authors: H
authors: Rosing
authors: Mona
authors: M
authors: Darwish
authors: Denise
authors: D
authors: D'Andrea
authors: Mary
authors: M
authors: Bond
authors: Edward
authors: E
authors: Hellriegel
authors: Philmore
authors: P
authors: Robertson
authors: Jos H
authors: JH
authors: Beijnen
authors: Jan H M
authors: JH
authors: Schellens
mesh_terms: D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine*; D000069461:Bendamustine Hydrochloride; D002250:Carbon Radioisotopes / Q000652:urine; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000652:urine*; D009369:Neoplasms / Q000188:drug therapy / Q000652:urine*; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine*; D012008:Recurrence
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002250:Carbon Radioisotopes; D009588:Nitrogen Mustard Compounds; D000069461:Bendamustine Hydrochloride