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Japanese Journal of Clinical Oncology Advance Access published online on June 23, 2005
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyi110
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© 2005 Foundation for Promotion of Cancer Research
Received March 15, 2005
Accepted May 15, 2005

Original Article

An Evaluation of Busulfan Pharmacokinetics in Patients Undergoing Hematopoietic Stem Cell Transplantation

Yasushi Takamatsu 1*, Kentaro Ogata 2, Keita Yamauchi 3, Shuuji Hara 3, Tomohiko Kamimura 4, Shin Hayashi 4, Junji Suzumiya 1, and Kazuo Tamura 1

1 First Department of Internal Medicine, Fukuoka University Hospital, Fukuoka, Japan
2 Department of Pharmacology, Fukuoka University Hospital, Fukuoka, Japan
3 Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
4 Department of Hematology, Hara Sanshin Hospital, Fukuoka, Japan

* To whom correspondence should be addressed.
Yasushi Takamatsu, E-mail: yasushi{at}fukuoka-u.ac.jp


  Abstract

Background: Busulfan (BU) pharmacokinetics (PK) are shown to be highly variable and thus their evaluation is critical for the success of hematopoietic stem cell transplantation (HST) in Caucasians. However, there are no data available for Japanese patients.

Methods: BU PK were evaluated in seven Japanese adult patients who underwent allogeneic HST. Four patients received 16 doses of 1 mg/kg of oral BU every 6 h for over 4 days followed by 120 mg/kg of intravenous cyclophosphamide, while three patients were given eight doses of 1 mg/kg of oral BU over 2 days in addition to 180 mg/kg of intravenous fludarabine with or without 2 Gy of total body irradiation. Blood samples were collected for PK analysis after the sixth dose of BU was administered.

Results: The average plasma BU concentrations at steady state (Css) ranged from 745 to 2422 ng/ml. Four of seven patients had BU Css >1000 ng/ml, the previously defined concentration associated with an increased risk of regimen-related toxicity (RRT). Indeed, one of them developed hepatic veno-occlusive disease. On the other hand, no severe toxicity greater than grade II except stomatitis was observed in the remaining patients whose Css were <1000 ng/ml.

Conclusion: A possible increased risk of RRT associated with high plasma BU concentrations should be kept in mind after oral administration of BU. A prospective trial of adjusting BU doses depending on the BU PK is warranted for Japanese patients.

Keywords: busulfan; pharmacokinetics; regimen-related toxicity; veno-occlusive disease.
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