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
The overall goal was to develop individualized dosing guidelines for the sedatives propofol and midazolam in infants and in critically ill patients, on the basis of population pharmacokinetic... Show moreThe overall goal was to develop individualized dosing guidelines for the sedatives propofol and midazolam in infants and in critically ill patients, on the basis of population pharmacokinetic-pharmacodynamic (PK-PD) modeling. Both under- and oversedation significantly and adversely affects patient outcome. Due to the high intra- and interindividual variability in dose requirements dosing is complicated. In this thesis the interindividual variability in response has been examined by covariate analysis. In this analysis the effects of bodyweight, cardiac function, severity of illness and liver blood flow and the unexplained interindividual variability have been characterized. It was shown that infants require higher doses of propofol because of differences in pharmacokinetics rather than pharmacodynamics. When comparing the results of the PK-PD model of propofol and midazolam in infants, propofol is preferred over midazolam because of the lower interindividual variability in pharmacodynamics compared to midazolam. In critically ill patients severity of the illness was found to be a major determinant of the level of sedation, with lower propofol dosing requirements with increasing severity of illness. The PK-PD models can be used as a basis for individualized dosing of propofol and midazolam, which is essential for optimizing the quality of sedation in clinical practice and will improve patients__ outcome. Show less
