Linearity and stability of intravenous busulfan pharmacokinetics and the role of glutathione in busulfan elimination

Shlomo Almog, Daniel Kurnik, Avichai Shimoni, Ronen Loebstein, Eyal Hassoun, Asher Gopher, Hillel Halkin, Arnon Nagler

Research output: Contribution to journalArticlepeer-review

Abstract

High-dose busulfan (Bu) is frequently used in preparative myeloablative conditioning (MAC) regimens for patients undergoing hematopoietic stem cell transplantation (HSCT). MAC and reduced-intensity conditioning (RIC) protocols for i.v. Bu infusion have been developed to achieve reliable systemic exposure while minimizing toxicity and treatment failure (relapse). The objectives of the present study were to (1) compare the pharmacokinetics (PK) of i.v. Bu in different dosing protocols, (2) compare intrasubject variability of Bu PK over repeated administrations; (3) examine the effect of concomitant administration of fludarabine on Bu PK, and (4) examine the effect of plasma concentrations of glutathione (GSH), the cosubstrate in Bu metabolism, on Bu clearance. We studied Bu PK twice in each of 46 HSCT patients (after the first and then after the middle dose of the treatment cycle) receiving one of 4 dosing protocols, 2 MAC (cumulative dose, 12.8 mg/kg) and 2 RIC (cumulative dose, 6.4 mg/kg), with daily doses administered either as an individual infusion (3.2 mg/kg) or as 4 infusions of 0.8 mg/kg each. Blood samples were obtained for 6-24 hours after dosing for measurement of Bu plasma concentrations. PK parameters were estimated using compartmental analyses. In a subgroup of patients (n = 14), GSH blood concentrations were determined before Bu administration. Dose- and weightcorrected Bu PK parameters (clearance, 0.173 ± 0.051 L/hour · kg; volume of distribution, 0.7±0.17 L/kg; half-life time, 3.0 ± 0.7 hours) did not differ among treatment protocols (all P>14) and remained stable between the first and mid-cycle doses. Fludarabine did not affect Bu PK. Blood GSH concentrations before Bu dosing were positively correlated with Bu clearance (adjusted R2 = 0.45; P5=.009). Our data indicate that Bu PK parameters are linear, stable, and predictable in different i.v. protocols and are unaffected by coadministration of fludarabine. Differences in whole blood GSH might contribute to variability in Bu clearance.

Original languageEnglish
Pages (from-to)117-123
Number of pages7
JournalBiology of Blood and Marrow Transplantation
Volume17
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • Bone marrow transplantation
  • Clearance
  • Conditioning regimen
  • Fludarabine
  • Oxidative stress

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