title: Population pharmacokinetic analysis of topotecan in pediatric cancer patients.
abstract: OBJECTIVE
  To characterize the population pharmacokinetics of topotecan lactone in children with cancer and identify covariates related to topotecan disposition.
  
  
  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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Schaiquevich
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Iacono
authors.forename: Burgess B
authors.initials: BB
authors.lastname: Freeman
authors.forename: Victor M
authors.initials: VM
authors.lastname: Santana
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D019772:Topotecan