Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; an alliance study (CALGB 10503, 19808, and 100103)
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Older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome have often been excluded from myeloablative-conditioning regimens containing busulfan because of non-disease-related morbidity and mortality. We hypothesized that busulfan clearance (BuCL) in older patients (>60 years) would be reduced compared to that in younger patients, potentially explaining observed differences in busulfan tolerability.
AML patients in three CALGB hematopoietic cell transplantation studies were treated with a conditioning regimen using IV busulfan, dosed at 0.8 mg/kg. Plasma busulfan concentrations were determined by LC–MS and analyzed by non-compartmental methods. BuCL was normalized to actual (ABW), ideal (IBW), or corrected (CBW) body weight (kg). Differences in BuCL between age groups were examined using the Wilcoxon rank sum test.
One hundred and eighty-five patients were accrued; 174 provided useable pharmacokinetic data. Twenty-nine patients ≥60 years old (median 66; range 60–74) had a significantly higher BuCL versus those <60 years old (median 50; range 18–60): BuCL 236 versus 168 mL/min, p = 0.0002; BuCL/ABW 3.0 versus 2.1 mL/min/kg, p = 0.0001; BuCL/IBW 3.8 versus 2.6 mL/min/kg, p = 0.0035; BuCL/CBW 3.4 versus 2.6 mL/min/kg, p = 0.0005. Inter-patient variability in clearance (CV %) was up to 48 % in both age groups. Phenytoin administration, a potential confounder, did not affect BuCL, regardless of weight normalization (p > 0.34).
Contrary to our hypothesis, BuCL was significantly higher in older patients compared to younger patients in these studies and does not explain the previously reported increase in busulfan toxicity observed in older patients.
KeywordsBusulfan Bone marrow transplant Elderly Pharmacokinetics
We thank the University of Pittsburgh Cancer Institute Hematology/Oncology Writing Group for constructive suggestions regarding the manuscript. This project used the UPCI Clinical Pharmacology Analytical Facility (CPAF) and was supported in part by award P30CA047904 (Jan H. Beumer). (Alliance) was supported, in part, by grants from the National Cancer Institute (CA31946) to the Alliance for Clinical Trials in Oncology (Monica M. Bertagnolli, M.D., Chair) and to the Alliance Statistics and Data Center (Daniel J. Sargent, Ph.D., CA33601). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. The following institutions participated in this study: Christiana Care Health Services, Inc. CCOP, Wilmington, DE, Stephen Grubbs, M.D., supported by CA45418; Dana-Farber Cancer Institute, Boston, MA, Harold J. Burstein, M.D., Ph.D., supported by CA32291; Monter Cancer Center of North Shore—LIJ Health Systems, Lake Success, NY, Daniel Budman, MD, supported by CA35279; Massachusetts General Hospital, Boston, MA, Jeffrey W. Clark, M.D., supported by CA32291; Mount Sinai Medical Center, Miami, FL, Michael A. Schwartz, M.D., supported by CA45564; The Ohio State University Medical Center, Columbus, OH, Clara D. Bloomfield, M.D., supported by CA77658; Rhode Island Hospital, Providence, RI, William Sikov, M.D., supported by CA08025; Roswell Park Cancer Institute, Buffalo, NY, Ellis Levine, M.D., supported by CA59518; University of California at San Francisco, San Francisco, CA, Charles J. Ryan, M.D., supported by CA60138; University of Chicago, Chicago, IL, Hedy L. Kindler, M.D., supported by CA41287; University of Maryland Greenebaum Cancer Center, Baltimore, MD, Martin Edelman, M.D., supported by CA31983; University of Massachusetts Medical School, Worcester, MA, William V. Walsh, M.D., supported by CA37135; University of Minnesota, Minneapolis, MN, Bruce A. Peterson, M.D., supported by CA16450; University of Nebraska Medical Center, Omaha, NE, Apar Ganti, M.D., supported by CA77298; University of North Carolina at Chapel Hill, Chapel Hill, NC, Thomas C. Shea, M.D., supported by CA47559; University of Vermont, Burlington, VT, Steven M. Grunberg, M.D., supported by CA77406; Wake Forest University School of Medicine, Winston-Salem, NC, David D. Hurd, M.D., supported by CA03927; Washington University School of Medicine, St. Louis, MO, Nancy Bartlett, M.D., supported by CA77440; Weill Medical College of Cornell University, New York, NY, John Leonard, M.D., supported by CA07968; Western Pennsylvania Cancer Institute, Pittsburgh, PA, John Lister, M.D., supported by CA31946; Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, NH, Konstantin Dragnev, M.D., supported by CA04326; Walter Reed Army Medical Center, Washington, DC, David C. Van Echo, M.D., supported by CA26806.
Conflict of interest
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