Proof of Concept in Assignment of Within-Subject Variability During Virtual Bioequivalence Studies: Propagation of Intra-Subject Variation in Gastrointestinal Physiology Using Physiologically Based Pharmacokinetic Modeling

While the concept of ‘Virtual Bioequivalence’ (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dep...

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Vydáno v:The AAPS journal Ročník 24; číslo 1; s. 21
Hlavní autoři: Bego, Margareta, Patel, Nikunjkumar, Cristofoletti, Rodrigo, Rostami-Hodjegan, Amin
Médium: Journal Article
Jazyk:angličtina
Vydáno: Cham Springer International Publishing 05.01.2022
Springer
Témata:
Adolescent
Adult
Biochemistry
Biological Availability
Biomedical and Life Sciences
Biomedicine
Biotechnology
Cross-Over Studies
Delayed-Action Preparations
Gastrointestinal Tract - physiology
Humans
Male
Medical research
Medicine, Experimental
Middle Aged
Models, Biological
Pharmacology/Toxicology
Pharmacy
Physiological aspects
Posaconazole
Proof of Concept Study
Research Article
Research Design
Theme: Integrating In Vitro Systems and Physiologically-Based Pharmacokinetics Modeling to Optimize Drug Product Development
Therapeutic Equivalency
Triazoles - administration & dosage
Triazoles - pharmacokinetics
Young Adult
intra-subject variation
virtual bioequivalence
physiology-based pharmacokinetics
within-subject variability
ISSN:1550-7416, 1550-7416
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Shrnutí:While the concept of ‘Virtual Bioequivalence’ (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as ‘not plausible’. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations. Graphical Abstract
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Guest Editors: Rodrigo Cristofoletti and Lawrence Yu
ISSN:1550-7416
1550-7416
DOI:10.1208/s12248-021-00672-z