Poster Presentation Advances in Neuroblastoma Research Congress 2016

Busulfan and melphalan pharmacokinetics in high-risk neuroblastoma patients treated on the HR-NBL1/SIOPEN trial (#308)

Gareth Veal 1 , Angelo Paci 2 , Vianney Poinsignon 2 , Julie Errington 1 , Jennifer Bonner 1 , Claudia Pasqualini 2 , Dominique Valteau-Couanet 2 , Martin Elliot 3 , Deborah Tweddle 1 , Ruth Ladenstein 4
  1. Newcastle University, Newcastle Upon Tyne, United Kingdom
  2. Institut Gustave Roussy, Villejuif, France
  3. Leeds General Infirmary, Leeds, UK
  4. St Anna Children’s Hospital and Children’s Cancer Research Institute, Vienna, Austria

Background Busulfan and melphalan (BuMel) are established as the high-dose chemotherapy regimen of choice in the HR-NBL1/SIOPEN trial. Previous studies have reported marked inter-patient variability in the pharmacokinetics of both drugs in various tumour types. The current study reports on BuMel pharmacokinetics in patients treated on the HR-NBL1/SIOPEN trial.

Methods Busulfan was administered 4xdaily for 4 days, either orally (doses of 1.45-1.55mg/kg) or IV (doses of 0.8-1.2 mg/kg according to body weight strata). Blood samples were obtained at 2-6h after the start of infusion or oral administration for dose 1. Melphalan was administered as an IV short infusion of 140mg/m2 (4mg/kg for patients <12kg) with samples collected at 5, 23 and 90min. Busulfan and melphalan levels were quantified by GCMS and HPLC analysis, respectively. Data were analysed using NONMEM population pharmacokinetic approaches.

Results Busulfan plasma concentrations obtained from 82 patients and melphalan data from 55 patients were fitted using one- and two-compartment pharmacokinetic models, respectively. A mean busulfan AUC value of 1059±261µM.min (range:434-1954) was observed, with 71% of children achieving AUC values within the defined target of 900-1500µM.min (56% following oral dosing, 78% with IV dosing). Busulfan AUC values in patients who experienced grade 3/4 non-haematological toxicity (n=47) were significantly higher than in patients with no grade 3/4 non-haematological toxicity (n=30) (1107±237 vs 960±251µM.min; P=0.027). A mean melphalan AUC of 10.9±6.0µg/ml.h (range:3.9-44.4) was observed, with a higher AUC in patients experiencing grade 3/4 VOD (n=7) than those with no VOD (n=31) (16.5±12.8 vs 9.7±3.9µg/ml.h; P=0.05). A significant difference in melphalan exposure was observed in children 2 (n=45) (7.4±2.6 vs 11.7±6.3µg/ml.h).   

Conclusions The data confirm higher and more consistent busulfan exposures with IV versus oral dosing and indicate a relationship between BuMel AUC and toxicity. Melphalan dosing based on body weight in children