Universiteit Leiden

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Optimisation of first clinical studies in special populations: towards semi-physiological pharmacokinetic models

M. Danhof, Co-promotores: J. Freijer, A. Yassen

Ashley Strougo Castelli de Souza
17 december 2015
Thesis in Leiden University Repository

Special populations are groups of patients that may respond differently to drug treatment due to a variety of factors, such as age or disease. Therefore, in drug development dedicated clinical studies are often required to determine the optimal dose for these (vulnerable) patient groups. Such studies are complicated by ethical and practical barriers that can hinder the objective of the study when not well designed. To optimise the design of such studies, the application of model-based approaches is essential. In this thesis, we aimed to develop a semi-physiological framework that constitutes a scientific basis for optimisation of study designs in special populations. First, we examined the accuracy of existing approaches in paediatric patients. For the "allometric scaling plus maturation function" approach, the accuracy was shown low especially in young children. An alternative approach was found in the physiological well-stirred-model of hepatic clearance. On this basis, the semi-physiological PK models were developed by interfacing descriptive compartmental pharmacokinetic models with the well-stirred-model of hepatic clearance, and a mechanistic description of plasma-protein binding. The performance of these models was evaluated using two paradigm-drugs (solifenacin and tamsulosin) and was shown successful for the prediction of the pharmacokinetics in paediatric, hepatic-impaired and renal-impaired patients.