Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation

Abstract

Summary:Published data suggest that the average concentration of busulfan at steady state (Bu Css) is critical for successful engraftment in children receiving busulfan as a conditioning agent for bone marrow transplantation (BMT). We previously found in children that a Bu Css Ͻ600 ng/ml correlated with autologous recovery/mixed chimerism; there was no correlation between Bu Css and regimen-related toxicity (RRT). In a cohort continuous with the previous trial, we prospectively evaluated targeted busulfan concentrations in 32 pediatric patients (age 0.6-18.5 years) with AML (n = 6), CML (n = 6) and non-malignant disorders (n = 20) receiving HLA-closely matched donor grafts. In this trial, individual busulfan pharmacokinetics were performed prior to admission. Busulfan doses were then adjusted to achieve a Bu Css target range of 600-900 ng/ml ± 10% depending on donor source and disease. A repeat study was done following dose 1 of the conditioning regimen. Thirty of thirty-two (94%) patients achieved target concentrations. Total busulfan doses ranged from 10.9 to 29 mg/kg. Thirty of thirty-two patients (94%) have durably engrafted. Grade 3/4 RRT occurred in seven patients (21%). Targeting Bu Css ranges of 600-900 ng/ml significantly improved our rate of successful engraftment from 74% to 94% (P = 0.043). These results indicate that targeted busulfan dosing optimizes allogeneic engraftment in children. Bone Marrow Transplantation (2001) 28, 1013-1018.

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

“…It has been reported that a high steady-state concentration of BU causes toxicities including VOD, 5-10 whereas a low steady-state concentration leads to graft rejection [10][11][12][13][14][15] or relapse/progression of the disease. 11 Targeted dose adjustment of BU to maintain the overall systemic exposure within a proper range may reduce these risks.…”

“…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.…”

Age-dependent pharmacokinetic profile of single daily dose i.v. busulfan in children undergoing reduced-intensity conditioning stem cell transplant

“…The upper limit of the BU therapeutic range in myeloablative transplantation is usually quoted as a total AUC of 21 600-24 000 mM min (that is, 1350-1500 mM min per dose  16 doses) and the lower limit, 14 400-16 000 mM min (900-1000 mM min per dose  16 doses). 12,31,34,[43][44][45][46] In the RIC regimens used in our study, the upper limits of total AUC were 9600 and 11 600 mM min in the first and second cohorts, respectively, and the lower limit, 6400 and 8400 mM min. The total BU exposure in our patients was only about half of that in patients who received myeloablative conditioning regimens.…”

“…31,46 It was estimated in these studies that there would be a graft failure rate of 10-20% if the steady-state concentration of BU dropped below 600 ng/ml (equivalent to an AUC at B900 mM min after an every 6-h dose). In more recent studies that used i.v.…”

“…8,30 Various targeted dosing strategies have been proposed to compensate for the age-dependent difference in BU PK profile. [31][32][33][34][35] In the past several years, the Children's Memorial Hospital SCT program has used reduced-intensity conditioning (RIC) regimens to prepare pediatric patients with malignant and nonmalignant diseases for HSPC transplantation. [36][37][38] The backbone of these regimens is comprised of i.v.…”