Modelling of Dexamethasone in Paediatric Leukaemia Patients using a Population Pharmacokinetic Approach
Martina Liebich (1), Rosanna K. Jackson (2), Julie A. E. Irving (2), Gareth J. Veal (2), Georg Hempel (1)
(1) Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Muenster, Muenster, Germany, (2) Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom
Objectives: Dexamethasone has been used as a central component in the treatment of childhood acute lymphoblastic leukaemia patients for several decades. However, relatively limited information about its pharmacokinetics in children has been published [1]. We conducted the current study to gain a deeper insight and understanding of dexamethasone pharmacokinetics in this vulnerable patient group.
Methods: Blood samples were collected from children enrolled in the UKALL 2011 Trial (EudraCT number: 2010-020924-22). Dexamethasone was administered orally at doses of 6 or 10 mg/m²/day. A total of 107 patients, 163 occasions and 668 blood samples were available for pharmacokinetic analysis. Modelling was performed using NONMEM 7.3 and diagnostic plots were created using R 3.3.2 and the xpose4 package.
Results: Median age and median weight for the studied population were 4.85 years and 19.0 kg, respectively. A one-compartment model with first-order absorption and elimination and proportional residual variability described the pharmacokinetics of dexamethasone adequately. As only oral data was available, volume of distribution and clearance were calculated as apparent volume of distribution and apparent clearance. Inter-individual variability was implemented on the apparent volume of distribution and the apparent clearance. Inclusion of allometric scaling was used to account for maturation processes among this patient population and substantially improved the model fit. Moreover, inter-occasional variability on clearance of dexamethasone was incorporated in the model explaining about half of inter-individual variability.
Conclusions: The pharmacokinetics of dexamethasone could be adequately described with our established model. The analysis provided a robust population pharmacokinetic model, which can be used to evaluate dosing regimens and covariate effects in children.
References:
[1] Jackson RK, Irving JA, Veal GJ. Personalization of dexamethasone therapy in childhood acute lymphoblastic leukaemia. Br J Haematol. 2016 Apr;173(1):13-24.