• EU - FP7 Integrated project
• Project: Predict-IV Profiling the toxicity of new drugs: a non animal-based approach integrating toxico-dynamics and biokinetics.
• Project coordinator: prof. Wolfgang Dekant, University of Würzburg, Germany.

The objective of Predict-IV is to provide an improved predictivity of the non-clinical safety testing well in advance of performing animal safety testing and clinical trials.

The aim of this specific PhD-project is to further develop the technique to measure absorption of compounds in vitro, measure metabolism and binding of the compounds to proteins in vitro and using these data to predict kinetic parameters in vivo.

Several pharmaceuticals are selected for measuring biokinetic parameters in vitro, including chlorpromazine and diazepam. Absorption of the compounds in the small intestine is measured in vitro using Caco-2 cell monolayers. These cells are derived from a human colon cancer and are used as a model to predict the absorption of compounds in vivo. The systems will be further adjusted to represent the in vivo situation as much as possible. Secondly, metabolism of the compounds is measured in vitro, either by using primary hepatocytes, liver cell lines or tissue slices.

In vivo, the compounds used in this project are highly bound to proteins in blood. Therefore, this should also be taken into account in in vitro tests. Binding of the compounds to albumin will be measured in vitro by using equilibrium dialysis.

With all the data gathered with the in vitro tests, a Physiologically Based BioKinetic (PBBK) model will be set up to extrapolate the in vitro data to the in vivo situation.

In early drug discovery, toxicity testing is one of the major bottlenecks, since these tests use a lot of animal experiments, they are time consuming and large amounts of the test compound are needed. In addition to investigating the possible toxicity of a compound, the pharmacokinetics are investigated in animals as well to obtain candidate compounds with desirable pharmacokinetics.

The combined use of in vitro and in silico methods could significantly reduce the use of animals by screening out drugs with undesirable properties prior to preclinical studies in animals.