Limited and optimal sampling strategies for etoposide and etoposide catechol in children with leukemia

Etoposide is used to treat childhood malignancies, and its plasma pharmacokinetics have been related to pharmacodynamic endpoints. Limiting the number of samples should facilitate the assessment of etoposide pharmacokinetics in children. We compared limited sampling strategies using multiple linear regression of plasma concentrations and clearance with Bayesian methods of estimating clearance using compartmental pharmacokinetic models. Optimal sampling times were estimated in the multiple linear regression method by determining the combination of two samples which maximized the correlation coefficient, and in the Bayesian estimation approach by minimizing the variance in estimates of clearance. Clearance estimates were compared to the actual clearances from Monte Carlo-simulated data and predicted clearances estimated using all available plasma concentrations in clinical data from children with acute lymphoblastic leukemia. Multiple linear regression poorly predicted clearance (mean bias 8.3%, precision 17.5%), but improved if plasma concentrations were logarithmically transformed (mean bias 1.4%, precision 12.5%). Bayesian estimation methods with optimal samples gave the best overall prediction (mean bias 2.5%, precision 6.8%) and also performed better than regression methods for abnormally high or low clearances. We conclude that Bayesian estimation with limited sampling gives the best estimates of etoposide clearance.