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. CONCLUSION: 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.