Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; an alliance study (CALGB 10503, 19808, and 100103)

• Published in: Cancer chemotherapy and pharmacology Vol. 74; no. 5; pp. 927 - 938
• Main Authors: Beumer, Jan H., Owzar, Kouros, Lewis, Lionel D., Jiang, Chen, Holleran, Julianne L., Christner, Susan M., Blum, William, Devine, Steven, Kolitz, Jonathan E., Linker, Charles, Vij, Ravi, Alyea, Edwin P., Larson, Richard A., Ratain, Mark J., Egorin, Merrill J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-11-2014; Springer; Springer Nature B.V
• Subjects: Acute Disease; Age Factors; Aged; Antineoplastic agents; Area Under Curve; Biological and medical sciences; Busulfan - blood; Busulfan - pharmacokinetics; Cancer Research; Female; General aspects; Hematopoietic Stem Cell Transplantation - methods; Humans; Leukemia, Myeloid - metabolism; Leukemia, Myeloid - therapy; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Clearance Rate; Middle Aged; Myeloablative Agonists - blood; Myeloablative Agonists - pharmacokinetics; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Bone marrow transplant; Busulfan; Pharmacokinetics; Elderly; Antineoplastic agent; Human; Acute myelogenous leukemia; Intravenous administration; Stem cell; Alkanediol; Hematopoietic cell; Malignant hemopathy; Alkanesulfonic acid; Alkylating agent; Nitrogen mustard; Bone marrow; Graft; Age; Hematopoietic stem cell transplantation; Cancer
• DOI: 10.1007/s00280-014-2571-0
• EISSN: 1432-0843
• ISSN: 0344-5704

Purpose
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.
Methods
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.
Results
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).
Conclusions
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.