Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation

Abstract

Busulfan is an alkylating agent that is widely used in preparative regimens for bone marrow transplantation (BMT). We developed a high-performance liquid chromatographic (HPLC) assay for the determination of plasma busulfan concentrations in 30 patients who received oral doses of 1 mg/kg. Concentrations were fit by a one-compartment pharmacokinetic model with first-order absorption. The pattern of absorption and elimination varied widely between patients, with peak concentrations ranging from 1.2 to 10.4 mumol/l (mean, 4.25 +/- 2.49). The elimination half-life ranged from 58 to 433 min (harmonic mean, 140 min). The AUC contributed by a single oral dose ranged from 606 to 5,144 mumol-min/l (mean, 2,012 +/- 1,223). Patients were evaluated for the development of veno-occlusive disease (VOD), a treatment complication that occurs in 20% of patients undergoing BMT and causes 10% of transplantation-related deaths. All six patients who developed VOD had an AUC greater than the mean, and five of them had an AUC that was greater than 1 SD above the mean. The occurrence of VOD was highly correlated with an increased AUC (greater than 1 SD above the mean) (X2 = 18; P less than 0.0001). Using multivariate logistic regression, no other statistically significant pharmacokinetic predictor of VOD was found. The tenfold variability in the busulfan AUC and the statistical association of increased AUC with the development of VOD suggest a possible role for therapeutic monitoring in this setting.

Busulfex (i.v. BU) and CY regimen before SCT: Japanese-targeted phase II pharmacokinetics combined study

“…11 Targeted dose adjustment of BU to maintain the overall systemic exposure within a proper range may reduce these risks. [4][5][6][7]14,15 Although it has been reported that there are ethnic differences in PK for a wide range of drugs, 28 this has not been seriously examined with i.v. BU.…”

“…1 To overcome the disadvantage of oral BU including gastrointestinal absorption, [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] i.v. BU was recently introduced into clinical use.…”

Exposure equivalence between IV (0.8 mg/kg) and oral (1 mg/kg) busulfan in adult patients

“…Renal elimination of Bu is known to be minor; about 2% of the unchanged drug is excreted in the urine [6,7]. The magnitude of inter-patient variation associated with oral Bu apparent clearance (CL/F) has been estimated at as high as 10-fold or more [7][8][9]. Patient characteristics and treatment co-factors have been studied for a better understanding of this high variability.…”

“…High values of areas under the plasma concentration-versus-time curve (AUC) have been related to an increased risk of severe regimen-related toxicities including hepatic veno-occlusive disease (VOD) [8,[12][13][14][15]. Conversely, low Bu AUCs have been correlated with an increased risk for graft rejection and leukaemia relapse.…”

Incidence and management of hepatic severe veno-occlusive disease in 273 patients in a single centre with defibrotide

“…Busulphanbased conditioning has previously been reported as the most important risk factor for VOD. 14 Wong et al 15 also found a 36% incidence of VOD in their series of 53 patients with myelofibrosis. As the FluBuATG regime is commonly used as the conditioning of choice for patients with myelofibrosis, 16 the risk of VOD in these patients is significantly increased.…”