Population Pharmacokinetic Analysis Of Topotecan In Pediatric Cancer Patients

Purpose: To characterize the population pharmacokinetics of topotecan lactone in children with cancer and identify covariates related to topotecan disposition. Patients and Methods: The study population consisted of 162 children in seven clinical trials receiving single agent topotecan as a 30-min infusion. A population approach via nonlinear mixed effects modeling was used to conduct the analysis. Results: A two-compartment model was fit to topotecan lactone plasma concentrations (n = 1874), and large pharmacokinetic variability was observed among studies, among individuals, and within individuals. We conducted a covariate analysis using demographics, biochemical data, trial effects, and concomitant drugs, The most significant covariate was body surface area, which explained 54% of the interinclividual variability for topotecan systemic clearance. Interoccasion variability was considerable in both clearance and volume (20% and 22%, respectively), but was less than interinclividual variability in both variables. Other covariates related to clearance were concomitant phenytoin, calculated glomerular filtration rate, and age (< 0.5 years). Including them in the model reduced the interinclividual variability for topotecan clearance by an additional 48% relative to the body surface area-normalized model. The full covariate model explained 76% and 50% of interinclividual variability in topotecan clearance and volume, respectively. Conclusions: We developed a descriptive and robust population pharmacokinetic model which identified patient covariates that account for topotecan disposition in pediatric patients. Additionally, dosing topotecan based on the covariate model led to a more accurate and precise estimation topotecan systemic exposure compared with a fixed dosing approach, and could be a tool to assist clinicians to individualize topotecan dosing.