Age Dependent Volume of Distribution of Pegylated Asparaginase (OncasparTM) in children and adults
S. Borghorst(1,2), N. Gökbuget(3), A. Niemann(1,2), C. Lanvers(2), G. Hempel(1,2)
(1) Department of Pharmaceutical and Medical Chemistry – Clinical Pharmacy, University of Muenster, Germany; (2) Department of Paediatric Haematology and Oncology, University Children’s Hospital Muenster, Germany; (3) Department of Internal Medicine II, Goethe University Hospital, Haematology/Oncology, Germany
Objectives: A higher volume of distribution normalized to body surface area (V/BSA) was reported for PEG-asparaginase in adults [1]. A Population pharmacokinetic (PopPK) analysis for PEG-asparaginase in children also identified a trend towards higher V/BSA with increasing age [2]. Therefore, we analysed serum activities from both children and adults to get a better insight into possible age dependent pharmacokinetics of PEG-asparaginase.
Methods: 2089 serum activity measurements in 449 patients aged 0.8 to 80.6 years (median age 27.1) from the paediatric ALL/NHL-BFM 95 and ALL/NHL-BFM REZ protocol as well as the adult GMALL 07/03 and GMALL Elderly 1/2003 protocol were analysed using nonlinear mixed effect modelling (NONMEM Vers. VI). Paediatric patients received 500, 750, 1,000 or 2,500 U/m2 PEG-asparaginase (OncasparTM) during induction and relapse treatment, adult dosage ranged from 500 to 2,000 U/m2.
Results: A one-compartment model with BSA as covariate for clearance (Cl) and volume of distribution (V) as well as Cl increasing with time best described the pharmacokinetics of PEG-asparaginase in children and adults. Age was included as categorical covariate on V for individuals younger than 18 years of age. Parameters found were: Vi= 3.48 l per 1.73m2 and Cl= 6.95 ml/h ± 58.1% per 1.73m2 (mean ± interindividual variability).
Conclusions: Children and adolescents younger than 18 years of age exhibit a significant lower volume of distribution normalized to BSA when compared to adults (1.05 vs 2.94 l/m2). The influence of age on dosing and schedule of PEG-asparaginase will be analysed in future studies.
References:
[1] Avramis VI, Spence SA. Clinical pharmacology of asparaginases in the United States: asparaginase population pharmacokinetic and pharmacodynamic (PK-PD) models (NONMEM) in adult and pediatric ALL patients. J Pediatr Hematol Oncol 2007 Apr; 29(4): 239-47.
[2] Hempel G, Müller HJ, Lanvers C, Würthwein G, Hoppe A, Boos J. A population pharmacokinetic model for pegylated asparaginase in children. British Journal of Haematology 2010 Jan;148(1):119-25.
