Linearity and Stability of Intravenous Busulfan Pharmacokinetics and the Role of Glutathione in Busulfan Elimination

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 weight-corrected Bu PK parameters (clearance, 0.173 ± 0.051 L/hour · kg; volume of distribution, 0.71 ± 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 R(2) = 0.45; P = .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.

Allogeneic hematopoietic SCT for adults AML using i.v. BU in the conditioning regimen: outcomes and risk factors for the occurrence of hepatic sinusoidal obstructive syndrome

“…This was also suggested in other studies. [21][22][23][40][41][42] Acute GVHD is related in part to tissue injury and cytokine release, 43,44 and limitation of tissue injury with this regimen may have contributed to this observation. However, severe acute GVHD remains a major obstacle to transplant success and better methods for GVHD prevention with preservation of antileukemic effects need to be explored.…”

“…BU 16,22,42 as there are many centers in Europe where BU levels are not Allo-SCT using i.v. BU conditioning in AML patients A Nagler et al measured.…”

Glutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation

“…12,13 Busulfan administration depletes the content of hepatocyte GSH, the co-factor of GST enzymes. 18,35 Plasma GSH correlates with busulfan clearance capacity 16 and hepatic GST activity negatively correlates with plasma busulfan and positively associates with its clearance. 14 In line with these data, the association between high busulfan plasma levels and post-transplant mortality has already been described.…”

“…15 Plasma GST activity and GSH level associate with the variability in busulfan clearance. 14,16 In this paper, 40 polymorphisms at 27 loci involved in hepatic glutathione balance 17 were studied in a total of 185 patients who underwent allogeneic HSCT from 2005 to 2009, after a busulfan-based preparative regimen (busulfan cohort). The impact of such loci was tested on overall survival, TRM, busulfan AUC and serum liver function tests.…”

Intravenous busulfan for autologous stem cell transplantation in adult patients with acute myeloid leukemia: a survey of 952 patients on behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

“…New modalities of administered intravenous busulfan are being tested with only one perfusion per day. 50 Likewise, high-dose melphalan is now given intravenously over 90 to 120 minutes. In the present study patients who received intravenous busulfan plus melphalan had a better overall survival rate than other patients but did not differ in terms of relapse incidence or leukemia-free survival rate.…”