This book focuses on novel approach to characterize developmental changes in pharmacokinetics across human lifespan with the up-to-date Nonlinear Mixed Effect Modeling techniques.
The maturation of UGT2B7-mediated drug glucuronidation was studied in preterm and term neonates up to infants of three years of age using a population approach. A pharmacokinetic model was... Show moreThe maturation of UGT2B7-mediated drug glucuronidation was studied in preterm and term neonates up to infants of three years of age using a population approach. A pharmacokinetic model was developed for morphine, which was used as a paradigm compound. In this model, the maturation of morphine glucuronidation is described by a bodyweight-based exponential relationship with an exponent of 1.44. The model-derived dosing algorithm was evaluated prospectively in a clinical trial and it was shown that this dosing algorithm may reduce overdosing of neonates and exposure to ineffective doses in older infants. Additionally, it was found that the bodyweight-based exponential relationship that describes the maturation of morphine glucuronidation can be directly applied to the maturation of zidovudine, which is also a UGT2B7 substrate. This expedites the development of paediatric pharmacokinetic models and evidence-based paediatric drug dosing algorithms. Based on a study using physiologically-based pharmacokinetic modeling it was concluded that the equation for maturation of morphine glucuronidation could be applicable to all small molecular drugs and to paediatric patient populations with normal hepatic function. Finally, a framework was developed to properly validate paediatric pharmacokinetic population models and the validation of paediatric pharmacokinetic models for morphine in literature were investigated. Show less
This thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis... Show moreThis thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis of potential improvements in risk stratification and possible treatment adaptation, in order to decrease relapse frequency and disease-related death. Firstly, to study the role of chemokine receptor/ligand interactions in the context of extramedullary leukaemia, we analyzed the homing receptor expression on leukemic blast cells in skin or intestine, peripheral blood and bone marrow of patients with T-ALL en AML, respectively. Secondly, the treatment results of 132 children, who received an allogeneic HLA-identical SCT for acute leukaemia was evaluated, showing the effect of biologically effective TBI dose on relapse risk. Thirdly, to optimize the use of Cyclosporin A(CsA) for adequate Graft-versus-host disease(GVHD) prophylaxis and to avoid drug toxicity, we investigated the pharmacokinetics of CsA in children after SCT, and showed that monitoring CsA exposure early after SCT may provide a tool to influence outcome. Finally, to gain a better understanding of the mechanism of chimerism induction of endothelial and epithelial cells following allogeneic SCT, the occurrence of chimerism in relation to the conditioning regimen, time interval after SCT and development of GVHD was studied. Show less
Epidural neural blockade results from processes after the administration of a local anaesthetic in the epidural space until the uptake in neural tissue. The pharmacokinetics, neural blockade and... Show moreEpidural neural blockade results from processes after the administration of a local anaesthetic in the epidural space until the uptake in neural tissue. The pharmacokinetics, neural blockade and haemodynamics after epidural anaesthesia may be influenced by several factors, with age as the most important one. Using the stable-isotope-method, the pharmacokinetics of the enantiomeric-pure local anaesthetics ropivacaine and levobupivacaine were derived and the influence of age on the pharmacokinetics was investigated. These local anaesthetics showed a bi-phasic absorption pattern. The fraction absorbed during the initial absorption process for levobupivacaine was low. The initial absorption parameters decreased with increasing age for epidurally administered levobupivacaine and ropivacaine.After epidural administration the level of analgesia was higher for levobupivacaine and ropivacaine and motor blockade was increased for ropivacaine in elderly patients. Haemodynamic changes, like the decrease in mean arterial pressure (MAP), were more pronounced in elderly patients after epidural administration of ropivacaine. It was postulated that this decrease is not only the result of the higher level of analgesia in elderly patients, but also from age-related changes in the cardiovascular and autonomic nervous system. Finally, a population pharmacokinetic/ pharmacodynamic model of the lumbar epidural space was developed that was able to demonstrate the importance of age on the spread of the sensory blockade as well as on the speed of onset/offset of blockade. Show less
