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

Abstract

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.

• Authors: Jan H Beumer, Kouros Owzar, Lionel D Lewis, Chen Jiang, Julianne L Holleran, Susan M Christner, William Blum, Steven Devine, Jonathan E Kolitz, Charles Linker, Ravi Vij, Edwin P Alyea, Richard A Larson, Mark J Ratain, Merrill J Egorin
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 74 Issue 5 Pg. 927-38 (Nov 2014) ISSN: 1432-0843 [Electronic] Germany
• PMID: 25163570 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Myeloablative Agonists
• Busulfan

Topics

• Acute Disease
• Age Factors
• Aged
• Area Under Curve
• Busulfan (blood, pharmacokinetics)
• Female
• Hematopoietic Stem Cell Transplantation (methods)
• Humans
• Leukemia, Myeloid (metabolism, therapy)
• Male
• Metabolic Clearance Rate
• Middle Aged
• Myeloablative Agonists (blood, pharmacokinetics)