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Population Pharmacokinetic Analysis of Topotecan in Pediatric Cancer Patients

Authors' Affiliations: Departments of ¹ Pharmaceutical Sciences and ² Oncology, St. Jude Children's Research Hospital, and Departments of ³ Pharmaceutical Sciences and ⁴ Pediatrics, University of Tennessee, Memphis, Tennessee

Requests for reprints: Clinton F. Stewart, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794. Phone: 901-495-3665; Fax: 901-525-6869; E-mail: clinton.stewart{at}stjude.org.

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 interindividual variability for topotecan systemic clearance. Interoccasion variability was considerable in both clearance and volume (20% and 22%, respectively), but was less than interindividual 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 interindividual 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 interindividual 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.