title: Design of a drug-drug interaction study of vincristine with azole antifungals in pediatric cancer patients using clinical trial simulation.
abstract: BACKGROUND
  The aim of the current work was to perform a clinical trial simulation (CTS) analysis to optimize a drug-drug interaction (DDI) study of vincristine in children who also received azole antifungals, taking into account challenges of conducting clinical trials in this population, and, to provide a motivating example of the application of CTS in the design of pediatric oncology clinical trials.
  
  
  METHODS
  A pharmacokinetic (PK) model for vincristine in children was used to simulate concentration-time profiles. A continuous model for body surface area versus age was defined based on pediatric growth curves. Informative sampling time windows were derived using D-optimal design. The CTS framework was used to different magnitudes of clearance inhibition (10%, 25%, or 40%), sample size (30-500), the impact of missing samples or sampling occasions, and the age distribution, on the power to detect a significant inhibition effect, and in addition, the relative estimation error (REE) of the interaction effect.
  
  
  RESULTS
  A minimum group specific sample size of 38 patients with a total sample size of 150 patients was required to detect a clearance inhibition effect of 40% with 80% power, while in the case of a lower effect of clearance inhibition, a substantially larger sample size was required. However, for the majority of re-estimated drug effects, the inhibition effect could be estimated precisely (REE < 25%) in even smaller sample sizes and with lower effect sizes.
  
  
  CONCLUSIONS
  This work demonstrated the utility of CTS for the evaluation of PK clinical trial designs in the pediatric oncology population.
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: J G Coen
authors.initials: JG
authors.lastname: van Hasselt
authors.forename: Natasha K A
authors.initials: NK
authors.lastname: van Eijkelenburg
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000935:Antifungal Agents / Q000378:metabolism / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000493:pharmacokinetics; D001393:Azoles / Q000378:metabolism / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D004340:Drug Contamination; D004347:Drug Interactions; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012107:Research Design; D014750:Vincristine / Q000378:metabolism / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D000972:Antineoplastic Agents, Phytogenic; D001393:Azoles; D014750:Vincristine
keywords: clinical trial simulation; pediatric oncology; pharmacokinetics; vincristine