Simultaneous confidence regions for multivariate bioequivalence

Pallmann, Philip Steffen and Jaki, Thomas Friedrich (2017) Simultaneous confidence regions for multivariate bioequivalence. Statistics in Medicine, 36 (29). pp. 4585-4603. ISSN 0277-6715

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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.

Item Type:
Journal Article
Journal or Publication Title:
Statistics in Medicine
Additional Information:
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. which has been published in final form at This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
Uncontrolled Keywords:
?? bioavailabilityjames-stein estimatorlimaçon of pascalsimultaneous inferencetostepidemiologystatistics and probability ??
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Deposited On:
04 Sep 2017 12:38
Last Modified:
31 Dec 2023 00:50