1. ¹Product Development Department, Pharmaceutical Division, Kirin Brewery Company Ltd, Shibuya-ku, Tokyo, Japan
2. ²Department of International Medicine and Molecular Science, Nagoya City University Graduate School of Medical Science, Mizuho-ku, Nagoya, Aichi, Japan
3. ³Hematopoetic Stem Cell Transplantation Unit, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan

Correspondence: H Takama, Product Development Department, Pharmaceutical Division, Kirin Brewery Company Ltd, 26-1 Jingumae 6-chome, Shibuya-ku, Tokyo 150-8011, Japan. E-mail: takamah@kirin.co.jp

Received 1 August 2005; Revised 7 November 2005; Accepted 11 November 2005; Published online 9 January 2006.

Abstract

A population pharmacokinetic analysis was performed in 30 patients who received an intravenous busulfan and cyclophosphamide regimen before hematopoietic stem cell transplantation. Each patient received 0.8 mg/kg as a 2 h infusion every 6 h for 16 doses. A total of 690 concentration measurements were analyzed using the nonlinear mixed effect model (NONMEM) program. A one-compartment model with an additive error model as an intraindividual variability including an interoccasion variability (IOV) in clearance (CL) was sufficient to describe the concentration–time profile of busulfan. Actual body weight (ABW) was found to be the determinant for CL and the volume of distribution (V) according to NONMEM analysis. In this limited study, the age (range 7–53 years old; median, 30 years old) had no significant effect on busulfan pharmacokinetics. For a patient weighting 60 kg, the typical CL and V were estimated to be 8.87 l/h and 33.8 l, respectively. The interindividual variability of CL and V were 13.6 and 6.3%, respectively. The IOV (6.6%) in CL was estimated to be less than the intraindividual variability. These results indicate high interpatient and intrapatient consistency of busulfan pharmacokinetics after intravenous administration, which may eliminate the requirement for pharmacokinetic monitoring.