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.
Yassen, A.; Passier, P.; Furuichi, Y.; Dahan, A. 2013
For most commonly used drugs in morbidly obese patients evidence based dosing guidelines are not available. Therefore, current dosing is based on experience of the prescriber rather than on... Show moreFor most commonly used drugs in morbidly obese patients evidence based dosing guidelines are not available. Therefore, current dosing is based on experience of the prescriber rather than on clinical evidence. Pharmacokinetic and pharmacodynamics data in non-obese patients are extrapolated without proper exploration of influence of overweight on the dose-exposure-effect relationship. The research described in this thesis focused on two commonly used drugs, propofol and the low-molecular-weight heparin (LMWH) nadroparin with the aim to develop weight appropriate dosing algorithms for these drugs in morbidly obese patients based on population pharmacokinetic and pharmacodynamics analysis. A non-linear relationship was found between propofol clearance and total body weight in both morbidly obese and non-obese adults, adolescents and children. Furthermore, the influence of age on propofol clearance was described using a bilinear function. A model based dosing algorithm using an adjusted dosing weight for propofol maintenance infusion was successfully evaluated in a prospective study in morbidly obese adults and can therefore be implemented in daily practice. For nadroparin in both morbidly obese and non-obese patients, total body clearance increased linearly with total body weight whereas the central of volume distribution increased linearly with lean body weight, suggesting that lean body weight is clinically useful for nadroparin dosing. The developed pharmacodynamic model for nadroparin in non-obese and morbidly obese patients can be used as a starting point to further identify the appropriate anti-Xa targets in morbidly obese patients. Show less
Hoch, M.; Hay, J.L.; Hoever, P.; Kam, M.L. de; Beek, E.T. te; Gerven, J.M.A. van; Dingemanse, J. 2013
This thesis covers a variety of topics around the central theme of pharmacological research involving children, with a specific focus on the development of minimally invasive methodology that can... Show moreThis thesis covers a variety of topics around the central theme of pharmacological research involving children, with a specific focus on the development of minimally invasive methodology that can be employed in future studies involving children. Children form a unique group within the area of pharmacological research and pharmacotherapy. The heterogeneity even within this group is large, covering the range of preterm neonates weighing 500 grams up to adolescents. Obviously, therapeutic needs change across this range, as among others disease epidemiology, drug disposition, pharmacodynamic response, and suitable drug formulations change with age. The same holds true for the design of drug trials involving children: where pharmacokinetics in adults can be studied simply by recruiting a number of healthy volunteers, such a study with a number of healthy toddlers is clearly not feasible and not acceptable. Therefore, approaches and new methodology are needed to circumvent these issues. Show less
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
Kasenda, B.; Rehberg, M.; Thurmann, P.; Franzem, M.; Veelken, H.; Fritsch, K.; ... ; Illerhaus, G. 2012
Calcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by... Show moreCalcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by serious clinical toxicity and between patient variability in their effect. Therefore, the dose of these drugs should be individualized in order to reach a balance between rejection and toxicity. This thesis aimed to describe the variability between and within patients using mathematical models and subsequently to explain this variability. Genetic and non-genetic factors were used to explain variability and several factors were identified (polymorphism in metabolism enzyme CYP3A5, body weight, concomitant prednisolone dose). For this purpose drug concentrations in blood are measured as a concentration biomarker. Furthermore, another biomarker the activity ot the target enzyme calcineurin was determined in leukocytes, but was found to be more variable within patients than between patients. This response biomarker was not found to be clinically useful to individualize the drug dosage. Finally, pharmacological determinants for subclinical acute rejection at 6 months were determined in patients treated with ciclosporin. Although ciclosporin exposure and several genetic variants were not found to relate, a previous acute rejection period and a kidney from a deceased donor increased the risk of rejection 5-fold. Show less
Dahan, A.; Olofsen, E.; Sigtermans, M.; Noppers, I.; Niesters, M.; Aarts, L.; ... ; Sarton, E. 2011
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
Protein binding can have major impact on a drug__s pharmacokinetics (PK) and pharmacodynamics (PD). At present the theoretical basis of the influence of (alterations in) plasma protein binding on... Show moreProtein binding can have major impact on a drug__s pharmacokinetics (PK) and pharmacodynamics (PD). At present the theoretical basis of the influence of (alterations in) plasma protein binding on pharmacokinetics is well-established. The role of plasma-protein binding on pharmacodynamics however has sofar not been established in a systematic manner. As such there is no scientific basis for the __free drug hypothesis__ which states that the pharmacological activity is correlated with unbound drug concentrations in plasma. The objective of the research described in this thesis is to determine, in a strictly quantitative manner, the influence of plasma protein binding on in vivo pharmacodynamics. To this end both in silico and in vivo investigations were performed using the beta-blockers as model compounds. In contrast to the PK, the free drug concentration is the main determinant of the PD under equilibrium conditions for both target and plasma protein. Moreover for the beta-blockers, the free plasma concentration appears to be the best predictor of in vivo PD. In case of a dynamic interaction, the probability of non-restrictive protein binding is (theoretically) higher with regard to the PD under certain conditions, but more extensive research is needed to confirm this statement. Show less
