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

Abstract

We studied the pharmacokinetic (PK) profile of single daily dose i.v. BU in children who underwent reducedintensity conditioning (RIC) transplantation. A cohort of 19 patients p4 years of age (group 1) and 33 patients 44 years (group 2) was studied. Patients received a BU test dose for PK studies, followed by two treatment doses adjusted to target an area under the curve (AUC) of 4000 lM min per day. Patients in group 1 attained a lower AUC as compared to group 2 (3568 vs 4035 lM min). In group 1, 67% patients and in group 2, 84% patients achieved AUC within the targeted range. Stable donor chimerism was achieved in 56% patients in group 1 and 79% in group 2. Eight patients required a second transplantation because of graft failure. Because of the concern that a low AUC adversely affected outcomes, a second cohort of 23 patients followed a modified protocol with a targeted AUC of 5000 lM min. A higher AUC was attained (4825 lM min). Stable donor chimerism was achieved in 91% of patients. Our results show that RIC regimens using two single daily doses of i.v. BU are effective in children, but a targeted AUC of 5000 lM min is recommended.

Single Daily Busulfan Dosing for Infants with Nonmalignant Diseases Undergoing Reduced-Intensity Conditioning for Allogeneic Hematopoietic Progenitor Cell Transplantation

“…Plasma was separated by centrifugation at 2500 rpm for 10 minutes at 4 C. Plasma was split into 2 equal amounts in 2 separate cryovials and stored at À20 C until the complete set of blood samples for each dose was obtained. The samples were shipped to the Seattle Cancer Care Alliance Clinical Pharmacokinetics Laboratory for determination of Bu AUC and clearance [4].…”

“…A patient's total exposure to Bu is an important parameter that guides its use: a higher-than-optimal exposure predisposes the patient to the toxic effects of the drug, whereas a suboptimal exposure increases the risk of graft failure [3]. The effective Bu exposure in patients who receive the drug could be highly variable, particularly in young children [4]. Unpredictable pharmacokinetic (PK) values are commonly seen after oral Bu doses in children [5][6][7], as erratic intestinal absorption of oral Bu and an age-dependent clearance of the drug contribute to a wide variability in effective Bu exposure [7,8].…”

“…One exception is in infant recipients, as infants generally have a faster clearance of the drug, thereby invalidating dosing conclusions drawn from i.v. Bu PK data obtained in adults or older children [4]. The best clinical strategy to ensure optimal Bu exposure in infants receiving i.v.…”

“…Bu as part of a reduced-intensity conditioning (RIC) regimen for pediatric patients [4,14]. To develop and validate a clinical strategy to optimally administer i.v.…”

Commentary

“…The logistics and costs associated with PK analysis continue to drive efforts investigating more efficient means to estimate busulfan dose (2)(3)(4). Careful consideration of the data from these studies is important.…”