Translational PKPD modeling in schizophrenia. Predicting human receptor occupancy

PhD ceremony: Mr. M.G. Johnson, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Translational PKPD modeling in schizophrenia. Predicting human receptor occupancy

Promotor(s): prof. G.M.M. Groothuis, prof. M. Danhof

Faculty: Mathematics and Natural Sciences

The research described in the thesis of Martin Johnson aims to develop a computer model to predict the level of receptor binding of a new anti schizophrenia drug, using in vitro data and data from animal experiments of a number of existing drugs.

Schizophrenia is a severe psychiatric illness, which affects approximately 1% of the population and usually becomes manifest between the 15th and 30th year of life. The symptoms as hallucinations and hearing voices can be reduced by antipsychotic drugs. These drugs are not always sufficiently effective against the various symptoms of schizophrenia. In the development of new medicines, it is difficult to predict whether they are effective, among others, because the efficacy is dependent on the amount of the drug that reaches the brain and binds to the dopamine receptors, resulting in a blockade of the receptor. The extent to which the dopamine receptors are blocked is crucial to the success of an anti-schizophrenic treatment.

The model developed by Johnson describes the transport of the drug to the brains, and the binding to the receptor and dissociation from the receptor. The model, developed with data for the rat, was then translated to predict the receptor occupancy in humans. It may be used for the selection of a suitable first dose in man in the development of new drugs and can also be used to design more informative and more efficient clinical trials.