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

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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.

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Acknowledgements

We are grateful to Drs. Michael Sorter and Drew Barzman of the Division of Child and Adolescent Psychiatry at Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA for sharing the age-weight data that were used in the external model validation.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH, 45229-3039, USA

    Min Dong, Tsuyoshi Fukuda & Alexander A. Vinks

  2. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Tsuyoshi Fukuda & Alexander A. Vinks

  3. Teva Pharmaceuticals, Frazer, PA, USA

    Sally Selim, Mark A. Smith & Laura Rabinovich-Guilatt

  4. Alexza Pharmaceuticals, Inc., Mountain View, CA, USA

    James V. Cassella

Authors
  1. Min Dong
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  2. Tsuyoshi Fukuda
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  3. Sally Selim
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  4. Mark A. Smith
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  5. Laura Rabinovich-Guilatt
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  6. James V. Cassella
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  7. Alexander A. Vinks
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Corresponding author

Correspondence to Alexander A. Vinks.

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Funding

This study was sponsored by Teva Branded Pharmaceutical Products R & D, Inc. and Alexza Pharmaceuticals. Both companies reviewed and approved the manuscript. Editorial assistance was provided by Peloton Advantage and was funded by Teva Branded Pharmaceutical Products R & D, Inc. (Frazer, PA, USA).

Conflict of interest

Min Dong has received a National Institute of Child Health and Human Development training grant (5T32HD069054) and is an employee of Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. Tsuyoshi Fukuda declares that he has no conflict of interest. Sally Selim and Laura Rabinovich-Guilatt are employees of Teva Pharmaceuticals and may hold stock/stock options in that company. Mark A. Smith was an employee of Teva Pharmaceuticals at the time of study conduct. James V. Cassella was an employee of Alexza Pharmaceuticals at the time of study design and conduct, and received consulting fees from Alexza Pharmaceuticals during manuscript review. Alexander A. Vinks has been a consultant for the study sponsor through a consulting agreement between Teva Pharmaceuticals and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Dong, M., Fukuda, T., Selim, S. et al. Clinical Trial Simulations and Pharmacometric Analysis in Pediatrics: Application to Inhaled Loxapine in Children and Adolescents. Clin Pharmacokinet 56, 1207–1217 (2017). https://doi.org/10.1007/s40262-017-0512-x

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  • DOI: https://doi.org/10.1007/s40262-017-0512-x

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