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    Rights statement: This is the peer reviewed version of the following article: Pallmann P, Jaki T. Simultaneous confidence regions for multivariate bioequivalence. Statistics in Medicine. 2017;36:4585–4603. https://doi.org/10.1002/sim.7446 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/sim.7446/abstract This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.

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Simultaneous confidence regions for multivariate bioequivalence

Research output: Contribution to journalJournal article

Published
<mark>Journal publication date</mark>20/12/2017
<mark>Journal</mark>Statistics in Medicine
Issue number29
Volume36
Number of pages19
Pages (from-to)4585-4603
Publication StatusPublished
Early online date30/08/17
<mark>Original language</mark>English

Abstract

Demonstrating bioequivalence of several pharmacokinetic (PK) parameters, such as AUC and Cmax, that are calculated from the same biological sample measurements is in fact a multivariate problem, even though this is neglected by most practitioners and regulatory bodies, who typically settle for separate univariate analyses. We believe, however, that a truly multivariate evaluation of all PK measures simultaneously is clearly more adequate. In this paper, we review methods to construct joint confidence regions around multivariate normal means and investigate their usefulness in simultaneous bioequivalence problems via simulation. Some of them work well for idealised scenarios but break down when faced with real-data challenges such as unknown variance and correlation among the PK parameters. We study the shapes of the confidence regions resulting from different methods, discuss how marginal simultaneous confidence intervals for the individual PK measures can be derived, and illustrate the application to data from a trial on ticlopidine hydrochloride. An R package is available.

Bibliographic note

This is the peer reviewed version of the following article: Pallmann P, Jaki T. Simultaneous confidence regions for multivariate bioequivalence. Statistics in Medicine. 2017;36:4585–4603. https://doi.org/10.1002/sim.7446 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/sim.7446/abstract This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.