© 2010 American Association for Clinical Chemistry, Inc.
Clinical Case Study |
Commentary
Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD.
aAddress correspondence to the author at: Johns Hopkins Medical Institutions, 600 N. Wolfe St./Meyer B-125, Baltimore, MD 21287. E-mail wclarke1{at}jhmi.edu.
Busulfan is a myeloablative agent that is used in combination with cyclophosphamide as a preparative regimen for bone marrow transplantation; high-dose busulfan can be used as a substitute for total body irradiation. The therapeutic window for busulfan is narrow, and the drug exhibits large pharmacokinetic variation (1). Overexposure to the drug produces toxic effects, including sinusoidal obstruction syndrome and gastrointestinal mucositis. Underexposure can cause relapse of the disease and/or graft rejection. This case described by Johnson-Davis et al. gives an excellent example of the role for busulfan monitoring in patient care and highlights 2 important points for therapeutic drug monitoring (TDM)—the role of TDM in individualized medicine and the importance of sample collection and handling.
Although pharmacogenomics continues to be the focus of discussions about personalized medicine, it is important to remember that nongenetic factors play a large role in drug disposition as well. In this particular case, busulfan is a substrate of cytochrome P450 3A4, and therefore its pharmacokinetics will be dependent to some degree on the genetic variation in this enzyme. This case, however, illustrates how drug–drug interactions and body composition can cause pharmacokinetic variation. These factors cannot be predicted from genetic analysis. Because of the influence of these nongenetic factors, TDM is needed for optimization (or personalization) of pharmacotherapy.
This case also illustrates the importance of sample collection and timing in TDM. When a sample is collected before the drug concentration in the patient reaches a steady state, dosage adjustments will be made with flawed information, in this case underestimating the patient’s exposure to busulfan and increasing the dose unnecessarily. Another important consideration is sample handling and the stability of the analyte. Busulfan is unstable at room temperature, and samples must be placed on ice immediately after collection and then stored at –20 °C until analysis (2). Failure to follow these guidelines will produce an underestimate of patient exposure, and potential overdosing of the patient.
Acknowledgments
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors’ Disclosures of Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.
References
- McCune JS, Holmberg LA. Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol 2009;5:957-969.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
- Balasubramanian P, Srivistava A, Chandy M. Stability of busulfan in frozen plasma samples and whole blood. Clin Chem 2001;47:766-768.
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