Despite the increasing number of obese patients, evidence-based dosing guidelines are scarce, particularly for obese children and morbidly obese adults (BMI > 40 kg/m2). For both these... Show more Despite the increasing number of obese patients, evidence-based dosing guidelines are scarce, particularly for obese children and morbidly obese adults (BMI > 40 kg/m2). For both these populations, pharmacokinetic studies are needed to provide a basis for evidence-based dosing guidelines. In this thesis, we studied the pharmacokinetics of the CYP3A substrate midazolam, the renally excreted drug metformin and acetaminophen (metabolized by glucuronidation, sulphation and CYP2E1) in obese adolescents and/or morbidly obese adults. We address several currently unanswered questions; Can doses for obese adolescents be predicted on the basis of data obtained in morbidly obese adults? How to analyse pharmacokinetic data in obese adolescents, for whom body weight is influenced by growth, age and obesity? How to achieve safe and effective acetaminophen dosing for morbidly obese patients? The studies described in this thesis contribute to the existing gaps in knowledge regarding the pharmacokinetics and evidence-based dosing of drugs in obese adolescents and morbidly obese adults. 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
