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Evaluation of a rate-adjusted area under the curve method to reduce the impact of variability in bioequivalence testing
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  • Adam Lucas,
  • Kayode Ogungbenro,
  • Shuying Yang,
  • Leon Aarons,
  • Chao Chen
Adam Lucas
Evotec UK Ltd
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Kayode Ogungbenro
University of Manchester
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Shuying Yang
GlaxoSmithKline
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Leon Aarons
University of Manchester, UK
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Chao Chen
GSK
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Abstract

Aim: To quantify the utility of the rate-adjusted area under the concentration curve method in increasing the probability of a correct and conclusive outcome of a bioequivalence (BE) trial for highly variable drugs when clearance (CL) varies more than volume of distribution (V). Methods. Data from a large population of subjects were generated with variability in CL and V parameters and used to simulate a two-period, crossover BE trial. The 90% confidence interval for formulation comparison was determined following BE assessment using the area under the concentration curve (AUC) ratio test, and the proposed rate-adjusted AUC ratio method. An outcome of bioequivalent, non-bioequivalent or inconclusive was then assigned in relation to predefined BE limits. Results: We illustrate the utility of the rate-adjusted AUC method for BE testing when CL varies more than V. The approach is expected to enhance the probability of correctly assigning BE or non-BE and to increase study power to further reduce the risk of an inconclusive trial. Conclusions: The rate-adjusted AUC method represents a simple and readily applicable approach to enhance the BE assessment of drug products when CL varies more than V.

Peer review status:IN REVISION

11 Nov 2020Submitted to British Journal of Clinical Pharmacology
13 Nov 2020Submission Checks Completed
13 Nov 2020Assigned to Editor
28 Nov 2020Reviewer(s) Assigned
29 Jan 2021Review(s) Completed, Editorial Evaluation Pending
05 Feb 2021Editorial Decision: Revise Major
04 May 20211st Revision Received
05 May 2021Submission Checks Completed
05 May 2021Assigned to Editor
05 May 2021Review(s) Completed, Editorial Evaluation Pending
23 May 2021Editorial Decision: Revise Major