New in vitro–in vivo simulations predict generic bioequivalence

Generics/Research | Posted 07/05/2021 post-comment0 Post your comment

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 [1], has been developed by researchers National and Kapodistrian University of Athens.

135 AA010177

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 [2] and the US Food and Drug Administration [3], 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.

GaBI Journal Citation Impact
1.7 – CiteScore 2019 (calculated on 6 May 2020)
1.9 – CiteScoreTracker 2020 (Last updated on 6 April 2021)

Submit a manuscript to GaBI Journal

Related articles
A blueprint for biosimilar assessment without efficacy trials

Certara technology achieves first FDA virtual bioequivalence approval for a complex generic drug

Computer modelling for glycoengineering of biosimilars


To further enhance the objectives of GaBI in sharing information and knowledge that ensure policies supportive of safe biosimilars use, we are pleased to announce that we will be launching a new section on GaBI Online and GaBI Journal, the ‘Latin American Forum’ (in Spanish) featuring the latest news and updates on research and developments in generic and biosimilar medicines in Latin America.

Register to receive the GaBI Latin American Forum newsletter. Inform colleagues and friends of this new initiative.



Para fomentar los objetivos de GaBI sobre la difusión de información y conocimiento sobre las políticas de apoyo que garantizan el uso seguro de medicamentos biosimilares, nos complace anunciar el lanzamiento de una nueva sección en GaBI Online y GaBI Journal, el ‘Latin American Forum’ (en español), que presentará las últimas noticias y actualizaciones en investigación y desarrollo sobre medicamentos genéricos y biosimilares en Latinoamérica.

Regístrese para recibir el boletín informativo GaBI Latin American Forum. Informe a colegas y amigos sobre esta nueva iniciativa. 

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 []. Mol, Belgium: Pro Pharma Communications International; [cited 2021 May 7].
Available from: 
3. GaBI Online - Generics and Biosimilars Initiative. US$1.2 FDA contract for generic drug computational tool []. Mol, Belgium: Pro Pharma Communications International; [cited 2021 May 7]. Available from:

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Copyright – Unless otherwise stated all contents of this website are © 2021 Pro Pharma Communications International. All Rights Reserved.

comment icon Comments (0)
Post your comment
Most viewed articles
About GaBI
Home/About GaBI Posted 06/08/2009
EU guidelines for biosimilars
EMA logo 1 V13C15
Home/Guidelines Posted 08/10/2010