Clinical pharmacology of etoposide in children undergoing autologous stem cell transplantation for various solid tumours

Abstract

1. The population pharmacokinetics of high-dose etoposide was studied in a group of young children and adolescents.

2. Twenty-six children and adolescent were administered high-dose etoposide as a continuous infusion over 24 h. Etoposide plasma concentration-time data was modelled using NONMEM^® 7. The effect of age, weight, serum creatinine (SCr), and gender on pharmacokinetic parameters (CL and V_d) were determined by a nonlinear mixed effect model.

3. The pharmacokinetics of etoposide based on BSA dosing was best described with a 1-compartment structural model which was parameterised in terms of clearance (CL) and volume of distribution (V_d). An exponential error model was used to explain intersubject variability and a proportional error model was used to describe residual or intrapatient variability. The final model parameter estimates for the typical (normalised to 70 kg) values of CL and V_d were 2.31 L/hr and 17.5 L, respectively. The CL and V_d allometrically increased with weight with the power of 3/4 and 1, respectively. After accounting for weight dependence using the allometric scaling, age, serum creatinine, and gender did not have any influence on model parameters.

4. The results of this children and adolescent population pharmacokinetic study indicates that etoposide pharmacokinetics were influenced by body weight on an allometric basis. The pharmacokinetic parameters CL and V_d increased with increasing weight similar to BSA.

Keywords::

• High-dose etoposide
• population pharmacokinetics
• weight-based dosing