Evaluation of area under the concentration curve adjusted by the terminal-phase as a metric to reduce the impact of variability in bioequivalence testing.
between occasion variability
bioequivalence
clearance
crossover
terminal-phase adjusted area under the concentration curve
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
29
06
2021
received:
12
11
2020
accepted:
05
07
2021
pubmed:
18
7
2021
medline:
12
4
2022
entrez:
17
7
2021
Statut:
ppublish
Résumé
To quantify the utility of a terminal-phase 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 the volume of distribution (V). Data from a large population of subjects were generated with variability in CL and V, and used to simulate a two-period, two-sequence 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 terminal-phase adjusted AUC ratio test. An outcome of bioequivalent, nonbioequivalent or inconclusive was then assigned according to predefined BE limits. When CL varied more than V, the proposed approach enhanced the probability of correctly assigning bioequivalent or nonbioequivalent and reduced the risk of an inconclusive trial. For a hypothetical drug with between-subject variability of 35% for CL and 10% for V, when the true test-reference ratio of bioavailability was 1.15, a crossover study of n = 14 subjects analysed by the proposed method would have 80% or 20% probability of claiming bioequivalent or nonbioequivalent, compared to 22%, 46% or 32% probability of claiming bioequivalent, nonbioequivalent or inconclusive using the standard AUC ratio test. The terminal-phase adjusted AUC ratio test represents a simple and readily applicable approach to enhance the BE assessment of drug products when CL varies more than V.
Substances chimiques
Tablets
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
619-627Informations de copyright
© 2021 British Pharmacological Society.
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