Which Dose of Busulfan Is Best?

Abstract

A 24-year-old woman with advanced Hodgkin disease received the standard dosing protocol for busulfan/cyclophosphamide before allogeneic hematopoietic stem cell transplantation (HSCT)1 from a matched unrelated donor. The target area under the plasma concentration vs time curve (AUC) for busulfan was set at 950 μmol · L−1 · min−1, near the low end of the therapeutic interval of 900–1350 μmol · L−1 · min−1. The patient’s body mass index (BMI) was 45.5 kg/m2 (height, 170.2 cm; weight, 132.0 kg), so the dose was based on the patient’s ideal body weight. The patient received 2-hour intravenous infusions of busulfan every 6 h for 4 days (16 doses total). The patient was concurrently prescribed multiple medications, including an immunosuppressant, an antiviral, an antifungal, an antidepressant, an anxiolytic, a β-blocker, and a muscle relaxant, as well as antibiotics, warfarin, opioids, and antiepileptic drugs. After the first dose (51 mg Busulfex®; Otsuka Pharmaceutical), timed plasma samples were collected after infusion to determine the AUC. Pharmacokinetics (PK) analysis was performed, and the AUC was determined to be 642 μmol · L−1 · min−1. According to these results, the predicted busulfan dosage required to achieve the target AUC was 75 mg per dose for the remaining 14 scheduled doses. Because of the large change in dosage, additional PK monitoring of busulfan was performed after the fifth dose (day 2). The fifth dose was selected to allow time to reach a steady-state concentration (Css) after the dosage adjustment and to avoid challenges in interpretation due to possible circadian variation in busulfan concentrations (1). Samples for monitoring were collected at the same time of day as the first monitoring dose. The AUC after the fifth dose was 1342 μmol · L−1 · min−1. On the …