In this thesis population pharmacokinetic and physiologically-based pharmacokinetic (PBPK) approaches were applied to investigate the influence of glomerular filtration (GF) and active tubular... Show moreIn this thesis population pharmacokinetic and physiologically-based pharmacokinetic (PBPK) approaches were applied to investigate the influence of glomerular filtration (GF) and active tubular secretion (ATS) on renal clearance in children. For this investigation, the contributions of passive (i.e. GF) and active (i.e. ATS) processes to renal clearance are considered. Both processes contribute to pediatric renal clearance and are expected to be influenced by developmental changes. Hence, the extent to which these developmental changes impact renal clearance is explored in pediatric populations using clinical data of existing drugs, and using a PBPK-based framework for hypothetical drugs with an array of different properties excreted by either GF or both GF and ATS. Show less
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... Show moreSpecial 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. Show less
