2011 - Athens - Greece

PAGE 2011: Oncology
Stephan Borghorst

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.

[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.

Reference: PAGE 20 (2011) Abstr 2186 [www.page-meeting.org/?abstract=2186]
Poster: Oncology
Click to open PDF poster/presentation (click to open)