Development and validation of limited sampling models for topotecan lactone pharmacokinetic studies in children

Purpose: To develop and validate a pharmacokinetic limited sampling model (LSM) for intravenous and oral topotecan pharmacokinetic studies in children. Methods: Topotecan lactone concentration-time data from five trials were used to develop and validate LSM for intravenous and oral topotecan. Based on full sampling from one intravenous study (30 patients; 195 studies), a LSM for intravenous topotecan was determined using a modification of the D-optimality algorithm. For oral topotecan we used full sampling data from one oral topotecan study (27 patients; 47 studies) to develop an LSM. Accuracy and bias of each LSM were determined relative to the full sampling method. Predictive performance of the LSM was validated using additional data and Monte–Carlo simulations based on these data. Results: LSM for intravenous topotecan includes: 5 min, 1.5, and 2.5 h after the end of the 30 min infusion. The median accuracy (absolute predicted error) and bias (predicted error) are ≤8% and ≤6.1%, respectively. For oral topotecan, the optimal LSM includes: 15 min, 1.5, and 6 h. The median accuracy and bias are 6% and 4%, respectively. Conclusions: Our results indicate that the optimal sampling times for the intravenous LSM for topotecan in children consist of: predose, and 5 min, 1.5, and 2.5 h after the end of infusion. For oral topotecan the sample times are predose, 15 min, 1.5, and 6 h after dose administration. These LSM are invaluable to children receiving topotecan because it minimizes inconvenience and blood collection.