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European Biopharmaceutical Review

When Oral Bioavailability Becomes a Problem

Florence Salmon, Miriam Verwei and Robert Havenaar of TNO discuss the importance of reliable preclinical prediction of bioavailability

Despite the use of numerous in silico tools during discovery and early development, many oral drugs still fail in the later stages of development due to their limited bioavailability. There is an increasing number of drugs with low bioavailability and, nowadays, a large part of newly-developed drugs are poorly soluble and/or permeable. For the further development of these drugs it is crucial to identify the limiting factors and to determine quantitatively which kinetic factors are responsible for this low bioavailability.

Due to large differences in physiology between animals and humans, the predictive value of preclinical animal studies is not always sufficient (1). The effect of food on the bioavailability of drugs in particular shows a large mismatch between results observed in animals and in humans. In principle, in vitro methods and in silico tools, whether or not they are used in combination, should have a better predictive value than animal studies regarding the overall bioavailability. Additionally, using an in vitro/in silico combination saves time and money, making a combined approach a valuable tool for pharmaceutical companies. By expanding the use of such combinations, the industry could limit the number of animal studies needed, whilst also reducing the number of bioavailability and bioequivalence studies in volunteers since only the most optimal formulation would be tested in vivo. This creates the opportunity to test innovative formulations as there is no need to prepare GMP compliant batches prior to in vitro testing.


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Florence Salmon was trained in Biochemistry and Analytical Organic Chemistry at the University of Strasbourg, France, where she obtained her PhD in 1991 on the enzymology of cholesterol biosynthesis. From 1991 to 1997 she worked at BASF-AG in Ludwigshafen, Germany, where she was in charge of setting up the in vitro ADME laboratory. Since 1997, Florence has been Head of the Pharmacokinetics and Metabolism department at TNO, where she is involved in research on disposition of numerous compounds, interspecies extrapolation of kinetics by PBPK-modelling, integrated PK/PD modelling and in vitro-in vivo correlation in metabolism.

Miriam Verwei studied Biology at the University of Utrecht, The Netherlands, after which she obtained her PhD in 2004 on the topic prediction of bioavailability using an integrated approach of in vitro studies and kinetic modelling. Since 2004 she has worked as a Project Leader within the field of kinetics and metabolism at TNO. Miriam is involved in several projects related to in vitro bioavailability research, including studies with the dynamic gastrointestinal model, intestinal cell lines, transporter systems, in vitro-in vivo extrapolation and PBPK modelling.

After veterinary training at the University of Utrecht, The Netherlands, Robert Havenaar studied for his PhD at the Medical Faculty in Utrecht on oral microbiota and sugar substitutes. He worked as a postdoctoral researcher on the maturation of intestinal microbiota in relation to gastrointestinal health at the Veterinary School, Utrecht. In 1988 he moved to TNO in Zeist for research on beneficial bacteria, including GMOs for animals and humans in relation to gastrointestinal health and safety. In 1993 Robert initiated the development and validation of the TNO dynamic gastrointestinal models, known as ‘the TIM systems’, together with Mans Minekus. Currently he is Technology Manager of a group of 16 scientists and technicians working with TIM systems on contract research projects for international food and pharma companies.

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Florence Salmon
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Miriam Verwei
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Robert Havenaar
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