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Population Pharmacokinetic-Based Dosing of Intravenous Busulfan in Pediatric Patients

From the US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Clinical Pharmacology (Dr Booth, Dr Rahman, Dr Sahajwalla, Dr Mehta, Dr Gobburu); US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Oncology Drug Products, Division of Drug Oncology Products (Dr Dagher); National Institutes of Health, National Cancer Institute, Division of Cancer Prevention, Gastrointestinal and Other Cancers Research Group (Dr Griebel); independent consultant, oncology and transplant, Minnesota (Dr Lennon); and Genzyme Europe Research, Cambridge, United Kingdom (Dr Fuller).

The objective of this study was to characterize the pharmacokinetics (PK) of intravenous busulfan in pediatric patients and provide dosing recommendations. Twentyfour pediatric patients were treated with intravenous busulfan, 1.0 or 0.8 mg/kg for ages 4 years or >4 years, respectively, 4 times a day for 4 days. Dense PK sampling was performed. Body weight, age, gender, and body surface area were explored for effects on PK, and Monte Carlo simulations were performed to assess different dosing regimens. The PK of intravenous busulfan was described by a 1-compartment model with clearance of 4.04 L/h/20 kg and volume of distribution of 12.8 L/20 kg. Simulations indicated that the mg/kg and mg/m² regimens were similar and achieved the desired target exposure in approximately 60% of patients. This model suggests that patients 12 kg should be dosed at 1.1 mg/kg and those >12 kg dosed at 0.8 mg/kg. Therapeutic drug monitoring and dose adjustment will further improve therapeutic targeting.

Key Words: Busulfan • pharmacokinetics • dosing • modeling • pediatrics

Address for reprints: Brian P. Booth, Food and Drug Administration, Office of Clinical Pharmacology, Division of Clinical Pharmacology 5, 10903 New Hampshire Avenue, Building 21, Room 3668, Silver Spring, MD 20993-0002.

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