Population pharmacokinetic analysis of topotecan in pediatric cancer patients

PAULA SCHAIQUEVICH; JOHN C PANETTA; LISA C IACONO; BURGESS B FREEMAN; VICTOR M SANTANA; AMAR GAJJAR; CLINTON F STEWART

CLINICAL CANCER RESEARCH

American Association for Cancer research

Año: 2007 vol. 13 p. 6703 - 6711

1557-3265

Purpose:To characterize the population pharmacokinetics of topotecan lactone in children withcancer and identify covariates related to topotecan disposition.Patients and Methods: The study population consisted of 162 children in seven clinical trialsreceiving single agent topotecan as a 30-mininfusion. Apopulation approach via nonlinearmixedeffects 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 indivi-duals, and within individuals.We conducted a covariate analysis using demographics, biochem-ical data, trial effects, and concomitant drugs. The most significant covariate was body surfacearea, which explained 54% of the interindividual variability for topotecan systemic clearance.Interoccasion variability was considerable in both clearance and volume (20% and 22%, respec-tively), but was less than interindividual variability in both variables. Other covariates relatedto clearance were concomitant phenytoin, calculated glomerular filtration rate, and age(<0.5 years). Including them in the model reduced the interindividual variability for topotecanclearance by an additional 48% relative to the body surface area ^ normalized model. The fullcovariate model explained 76% and 50% of interindividual variability in topotecan clearanceand volume, respectively.Conclusions:We developed a descriptive and robust population pharmacokinetic model whichidentified patient covariates that account for topotecan dispositionin pediatric patients.Addition-ally, dosing topotecan based on the covariatemodel led to amore accurate and precise estimationtopotecan systemic exposure compared with a fixed dosing approach, and could be a tool toassist clinicians to individualize topotecan dosing.