Reiterated Therapeutic Drug Monitoring (TDM) Dosing to Significantly Improve the Control of Exposure to IV Busulfan in Infants and Older Children Undergoing Hematopoietic Stem-Cell Transplantation (HSCT)
Authors: Amin Alexandre , Bourget Philippe , Neven Benedicte , Fremond Marie-Louise , Castelle Martin , Elkaim Elodie , Cros Guilhem , Moshous Despina , Touzot Fabien , Lalli Alexandre , Petain Aurélie , Nguyen Laurent , Blanche Stephane 
Published: October 2019

Abstract
Introduction: Busulfan (Bu) is recognized worldwide as the cornerstone for HSCT conditioning regimens (CR). It has a narrow therapeutic window (TW), and graft rejection or toxicity are related to Bu exposure. In very young children, Bu exhibits large pharmacokinetic (PK) variability, and its metabolic clearance is non-linearly related to body weight (BW). In this setting, Bu dosage is stratified according to BW and commonly monitored once after the 1st of 16 total 2-hr infusions and finally, 96-hr exposure to this major alkylating agent. Given the narrow TW of Bu in relation to clinical outcomes and to better understand its PK/PD relationship, it is important to attempt to optimize both the duration and the intensity of exposure to Bu in children undergoing HSCT, whatever their BW and pathologies.
Study objective: To optimize Bu duration/intensity exposure in children undergoing HSCT, we studied the possible contribution of double TDM of IV Bu dosing in children receiving Bu-based CR for HSCT, by comparing the expected targeted values of exposure after performing 1 PK (1st dose, PK1) and finally 2 PK (1st dose, PK1, and 9th dose, PK2).
Patients and methods: In this single-centre* prospective observational study (05/2012-07/2015), the PK of Bu was performed using the NONMEM® software; a one-compartment PK model suitably fitted the concentrations vs. time data. The PK of Bu was assessed on 6 plasma samples (3 samples/PK) using a validated LC-MS/MS method, with area under the concentration-time curve (AUC) calculation from the 1st and 9th doses. AUC calculated after the 1st dose and extrapolated to the 16th one were compared intraindividually by the non-parametric Wilcoxon signed-rank test to the sum of AUC1-6 with TDM1 applied from the 7th dose with or without TDM2 applied from the 13th or 14th dose; p≤0.025 was considered statistically significant. 63 patients (Pts) undergoing HSCT were included with median follow up of 14 months [1-39]. Median age was 17 months [1-193] and BW 11 kg [3-59]. Most Pts had non-malignant diseases, received allogenic HSCT and Bu-based CR in combination with Flu (morphometric, disease and CR details will be provided).
*one of the 14 French Pediatric BMT units, involved in the therapeutic monitoring of IV Bu dosing in children undergoing HSCT.
Results: 63 Pts (37 males (59%) and 26 females (41%)) were included. According to the EBMT-ESID recommendations, a median Bu posology of 1 mg/kg 4x/day for 4 days [0.6-1.3 mg/kg] was given. We demonstrate that: (a) estimated total AUC obtained from 2 PK differ significantly from those calculated after none (p=8.6455 E-7) or PK1 alone (p=7.2157 E-8), (b) double TDM allows achieving no difference between the expected AUC [20,706-23,180 mmol/min] desired by the medical staff in view of diseases vs. estimated AUC (p=0.5285). In 2/63 (3.2%) Pts, PK analysis did not lead to change Bu dosage. In 11/63 (18%) and 15/63(24%) Pts, dosage was modified after PK1 (TDM1 Group) or PK2 alone, respectively. In 35/63 (56%) Pts, changes were required twice, after the 2 PK (Double-TDM Group). The mean total dose of Bu were as follows: (a) a theoretical value of 220.80 mg (20.11 mg/kg) would have been given through 16 consecutive infusions without any TDM, (b) 199.35 mg (18.08 mg/kg) were administered in the TDM1 Group (16 doses), (c) 246.00 mg (19.46 mg/kg) were administered in the Double-TDM Group, avoiding the infusion of 24.00 mg of Bu vs. PK1 alone in these Pts. In 16/63 (25%) Pts, a decision of discontinuation of Bu exposure was taken. Indeed, the value that was desired by the medical staff was achieved after 13 (6 Pts) or 14 (10 Pts) doses; the mean total amounts of Bu were 273.22 mg (14.96 mg/kg) and 225.88 mg (16.16 mg/kg), respectively, vs. 336.27 mg (18.45 mg/kg) and 262.56 mg (18.60 mg/kg) theoretically after TDM1 alone.
Conclusion: In this large paediatric cohort, the double TDM of Bu is a relevant and feasible option to better control Bu exposure and to potentially minimize the risk of overexposure. Correlations with toxicities (VOD, aGVH), CR, OS are under analysis. Based on these data, the double-TDM procedure is routinely applied in our centre.

Disclosures
Petain: Laboratoires Pierre Fabre: Employment. Nguyen:Laboratoires Pierre Fabre: Employment.