Many physiological processes, including those involved in the absorption, distribution, metabolism, elimination, pharmacodynamics and toxicity of therapeutic drugs, show profound fluctuations... Show moreMany physiological processes, including those involved in the absorption, distribution, metabolism, elimination, pharmacodynamics and toxicity of therapeutic drugs, show profound fluctuations over the course of the day and night. This may lead to time-of-day dependent changes in the exposure and effect of therapeutic drugs. The aim of this thesis is to provide a structured framework for chronopharmacological studies, while concurrently touching upon several critical issues encountered during the development and optimization of new and existing drug treatments. Firstly, we studied 24-hour variation in the pharmacokinetics of both midazolam and levofloxacin in healthy male subjects and found that for both drugs, absorptive processes show time-of-day dependency. Moreover, the magnitude of QT prolongation induced by levofloxacin, a common side-effect induced by many types of drugs, varied considerably and systematically over the course of the day. Furthermore, we investigated daily variation of drug distribution to the brain and found that time of day can be a considerable source of variation that could influence the effectiveness of drugs targeted to the brain. Taken together, these studies show that chronopharmacological aspects should not be overlooked in order to benefit from the systematic fluctuations in physiological processes during the development and optimization of drug treatments. Show less
This thesis focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is proposed to 1) ensure that... Show moreThis thesis focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is proposed to 1) ensure that pharmacological concepts are incorporated into the evaluation of safety and toxicity; 2) facilitate the integration of historical evidence and thereby the translation of findings across species; and 3) promote the use of experimental protocols tailored to address specific safety and toxicity questions. Nonlinear-mixed effects modelling is recommended as a tool to account for such requirements. Our goal was to explore the feasibility of a model-based approach to toxicology assessment and risk prediction in humans and, where possible, to compare the performance of this approach to traditional safety assessment approaches. The investigational plan of the thesis was divided into two sections where the development of methodology is followed by a case study with real data. A variety of analysis strategies and protocol designs are investigated where we set the constraint that proposals to deviate from existing protocols be minimal. We finally compile recommendations for protocol optimisation and data analysis/interpretation strategies to facilitate the implementation of model-based techniques in safety pharmacology and toxicology research 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
