Effect of age on the pharmacokinetics of busulfan (Bu): An alliance study.

Abstract

2533 Background: Older acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients (pts) have been excluded from myeloablative regimens including agents such as busulfan because of the potential for non-disease related morbidity and mortality. Busulfan, often used as part of myeloablative regimens, is cleared in part by glutathione–S-transferase and CYP3A4. We hypothesized that busulfan clearance (BuCL) in the elderly (> 60 years) would be reduced compared to that in young patients (< 60 years), thus potentially explaining differences in tolerability. Methods: AML and MDS pts in three CALGB bone marrow transplant studies across a wide age range (17-74) were treated with a conditioning regimen using IV busulfan, dosed at 12.8 mg/m2 in CALGB studies 10503 and 19808 and 6.4 mg/m2 in CALGB 100103. Blood samples were collected for determination of busulfan plasma pharmacokinetics (PK). Plasma busulfan was quantitated by LC-MS. BuCL was determined using non-compartmental modeling, and normalized to actual (ABW), ideal (IBW) and corrected (CBW) body weight (kg). Differences between age groups were examined using the Wilcoxon rank sum test. Results: A total of 185 pts were accrued and signed consent, of which 174 provided useable PK data. Twenty-nine pts ≥60 years old (median age 66.3) had a significantly higher mean BuCL vs those < 60 years old (median age 49.8); BuCL 263 vs 186 mL/min, p=0.0002; BuCL/ABW 3.22 vs 2.34 mL/min/kg, p=0.0001; BuCL/IBW 3.63 vs 2.91 mL/min/kg, p=0.0035; BuCL/CBW 3.50 vs 2.70 mL/min/kg, p=0.0005. Inter-patient variability in clearance (CV%) was up to 47% in the elderly and up to 48% in young patients. Phenytoin use, a potential confounder, did not affect BuCL, regardless of weight normalization (p=0.74). Conclusions: Contrary to our hypothesis, BuCL is significantly higher in pts ≥60 years old compared to younger patients and does not explain the previously reported increase in Bu toxicity observed in the elderly.