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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 10/2017

01-10-2017 | Original Research Article

Clinical Trial Simulations and Pharmacometric Analysis in Pediatrics: Application to Inhaled Loxapine in Children and Adolescents

Authors: Min Dong, Tsuyoshi Fukuda, Sally Selim, Mark A. Smith, Laura Rabinovich-Guilatt, James V. Cassella, Alexander A. Vinks

Published in: Clinical Pharmacokinetics | Issue 10/2017

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Abstract

Background and Objectives

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.

Methods

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.

Results

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).

Conclusion

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.
Appendix
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Metadata
Title
Clinical Trial Simulations and Pharmacometric Analysis in Pediatrics: Application to Inhaled Loxapine in Children and Adolescents
Authors
Min Dong
Tsuyoshi Fukuda
Sally Selim
Mark A. Smith
Laura Rabinovich-Guilatt
James V. Cassella
Alexander A. Vinks
Publication date
01-10-2017
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 10/2017
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-017-0512-x

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