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
Koskimaa, H.M.; Paaso, A.; Welters, M.J.P.; Grenman, S.; Syrjanen, K.; Burg, S.H. van der; Syrjanen, S. 2015
This thesis describes the potential role of non-invasive measurement of pharmacokinetics (pk) and pharmacodynamics (pd) in the research and development of central nervous system (cns) stimulants or... Show moreThis thesis describes the potential role of non-invasive measurement of pharmacokinetics (pk) and pharmacodynamics (pd) in the research and development of central nervous system (cns) stimulants or depressants for children and adolescents. First, we evaluated the feasibility of using saliva as an alternative to plasma in two studies on psychostimulants (caffeine and methylphenidate). Second, neuropsychological and neurophysiological functions were measured longitudinally using the NeuroCart, a battery of tests developed at the Centre for Human Drug Research (chdr, Leiden, The Netherlands) that includes non-invasive tests for alertness, visuomotor coordination, motor control, memory, and subjective drug effects. Using a non-invasive approach, age-dependent differences in alcohol pk and pd were evaluated between healthy adolescents and adults. This thesis concludes with the report of two clinical trials that were designed to evaluate age-appropriate formulations of sedative drugs that have the potential for use in children. Show less
Large numbers of children all over the world face significant health risks, such as infectious and chronic diseases, malnutrition, injuries and the consequences of natural disasters, protracted... Show moreLarge numbers of children all over the world face significant health risks, such as infectious and chronic diseases, malnutrition, injuries and the consequences of natural disasters, protracted armed conflicts and poverty. Every year, 4 million babies die within the first month of their life and almost 8 million children under the age of five die from preventable diseases such as malaria, pneumonia, measles and diarrhoea. These general statistics do not reveal the underlying inequalities in health between and within countries. One of the causes of the inequalities is that, in many countries, vulnerable groups of children have no or only limited access to health services. This research aims to identify the standards in international law for realizing the right to the highest attainable standard of health of the child. The central questions that are analysed: a. What priorities derive from the concept of the highest attainable standard of health of the child, its definition and the interpretation of the key constituent elements on the basis of international human rights law? b. How should this concept be implemented in the light of the international human rights standards? Show less
This descriptive and analytical study is based on two corpora of audiovisual data of monolingual and multilingual children’s babbling and first words gathered in Mali during a period of nearly a... Show moreThis descriptive and analytical study is based on two corpora of audiovisual data of monolingual and multilingual children’s babbling and first words gathered in Mali during a period of nearly a year. It is concerned with fundamental discussions about the development and acquisition of language such as the issue of the presence or absence of evidence of early specialization in children at the babbling stage, the continuity between babbling and first words, and the emergence and development of phonology in children Show less
This research offers a comprehensive analysis of the International Criminal Court (ICC) and its core legal texts from a children’s rights perspective. It examines the ICC provisions and its case... Show moreThis research offers a comprehensive analysis of the International Criminal Court (ICC) and its core legal texts from a children’s rights perspective. It examines the ICC provisions and its case law, evaluating whether these meet international children’s rights standards, particularly as regards the protection of child victims and witnesses, their participation as victims in ICC proceedings and their role as beneficiaries in reparations. The manuscript proposes recommendations that could be adopted in order to guarantee children’s rights in ICC proceedings. The research is a useful tool for practitioners as well as for academics, both in the area of international criminal law as well as children’s rights. Show less
