title: Development and validation of limited sampling models for topotecan lactone pharmacokinetic studies in children.
abstract: OBJECTIVE
  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 < or =8% and < or =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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: P Kellie
authors.initials: PK
authors.lastname: Turner
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Iacono
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Victor M
authors.initials: VM
authors.lastname: Santana
authors.forename: Najat C
authors.initials: NC
authors.lastname: Daw
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D006801:Humans; D007275:Injections, Intravenous; D015233:Models, Statistical; D009010:Monte Carlo Method; D015203:Reproducibility of Results; D013048:Specimen Handling; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan