title: Clinical Trial Simulations and Pharmacometric Analysis in Pediatrics: Application to Inhaled Loxapine in Children and Adolescents.
abstract: Loxapine for inhalation is a drug-device combination product approved in adults for the acute treatment of agitation associated with schizophrenia or bipolar I disorder. The primary objective of this study was to develop a clinical trial protocol to support a phase I pharmacokinetic study in children aged 10 years and older. In addition, this report details the results of the clinical study in relation to the predicted likelihood of achieving the target exposure associated with therapeutic effect in adults.
  
  
  
  A nonlinear mixed-effects population pharmacokinetic model was developed using adult data and was adjusted for the targeted pediatric age groups by applying allometric scaling to account for body size effects. Based on this pediatric model, age-appropriate regimens to achieve loxapine exposures similar to the ones associated with therapeutic effect in the adult studies were identified via trial simulation. D-optimal design and power analysis were conducted to identify optimal pharmacokinetic sampling times and sample size, respectively.
  
  
  
  The developed clinical trial design formed the basis of a phase I study to assess the safety and pharmacokinetics of loxapine for inhalation in children aged 10 years and older (ClinicalTrials.gov ID: NCT02184767).
  
  
  
  The results of the study indicated that overall loxapine exposures were consistent with what had been predicted by the trial simulations. The presented approach illustrates how modeling and simulation can assist in the design of informative clinical trials to identify safe and effective doses and dose ranges in children and adolescents.
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH, 45229-3039, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Dong
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH, 45229-3039, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Teva Pharmaceuticals, Frazer, PA, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Selim
authors.affiliation: Teva Pharmaceuticals, Frazer, PA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Teva Pharmaceuticals, Frazer, PA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Rabinovich-Guilatt
authors.affiliation: Alexza Pharmaceuticals, Inc., Mountain View, CA, USA.
authors.forename: James V
authors.initials: JV
authors.lastname: Cassella
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH, 45229-3039, USA. sander.vinks@cchmc.org.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. sander.vinks@cchmc.org.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008152:Loxapine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological
chemical_list: D014150:Antipsychotic Agents; D008152:Loxapine
keywords: Body Size Effect; Clinical Trial Simulation; Loxapine; Optimal Sampling Design; Target Exposure