If we can predict the outcome of bioequivalence studies in the generic drug development process, we can save time and money. Now, a new in vitro–in vivo simulation (IVIVS) approach to predict the in vivo outcome of these studies, published in Materials , has been developed by researchers National and Kapodistrian University of Athens.
Bioequivalence studies – the background
The aim of bioequivalence testing for generic drug products is to assess the in vivo equivalence between the active substance in the generic and the originator.
This is generally performed on the grounds of pharmacokinetics with proof of equivalence being extrapolated. In bioequivalence studies, the two products have the same active substance and differences are generally attributed to the absorption process which is impacted by the excipients and formulation.
So, understanding the in vitro drug release performance is key when it comes to bioequivalence. Information on this is thus important in research and development (R & D) processes and decisions on formulation. In vitro dissolution studies are commonly used here, and comparative dissolution studies provide useful insights to in vivo bioequivalence.
Computational approaches to development
Considering the above, the researchers developed a computational IVIVS approach to predict the in vivo outcome of bioequivalence studies which relies on in vitro dissolution data and literature information on in vivo pharmacokinetics.
The researchers note that computational methods are now widely used in pharmaceutical development. However, there remains a great need to expand the translation of in vitro data into in vivo performance to assist R & D and provide reliable predictions. This has led organizations such as the European Medicines Agency  and the US Food and Drug Administration , to take action to support the development of modelling aspects relevant to medicines.
A new IVIVS approach
In this current approach, the methodology is composed of three aspects: (i) mathematical description of in vitro dissolution profiles; (ii) mathematical description of in vivo kinetics; and (iii) development of joint in vitro–in vivo simulations. The
approach can be implemented for any number of subjects, clinical designs, variability and can be repeated for thousands of times. In each scenario, the probability of success is recorded which enables an overall assessment of batches to be made so that the most suitable can be selected. In cases where the IVIVS shows reduced probability of bioequivalence success, the R & D department will be advised to reformulate.
The team evaluated the predictability of the IVIVS procedure through its application in the development process of a new generic combination of three drugs (amlodipine/irbesartan/hydrochlorothiazide). Here, the bioequivalence predicted by IVIVS agreed with the findings of the actual bioequivalence study for all three compounds.
In conclusion, the team note that the IVIVS tool can help in pharmaceutical development by providing guidance to the R & D department on the likelihood of bioequivalence acceptance of a developed formulation. In addition, important aspects of the clinical design of future pivotal studies can be assessed, to ensure appropriate aspects such as sampling scheme and sample size. The predictability of these aspects can save both time and money in the development process.
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1. Marilena Vlachou M, Karalis V. An in vitro-in vivo simulation approach for the prediction of bioequivalence. Materials (Basel). 2021;14(3):555.
2. GaBI Online - Generics and Biosimilars Initiative. EMA-publishes-concept-paper-on-extrapolation [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 May 7].
Available from: www.gabionline.net/Policies-Legislation/EMA-publishes-concept-paper-on-extrapolation
3. GaBI Online - Generics and Biosimilars Initiative. US$1.2 FDA contract for generic drug computational tool [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 May 7]. Available from: www.gabionline.net/Generics/General/US-1.2-FDA-contract-for-generic-drug-computational-tool
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