The objective of this thesis was the development of a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the electro-encephalogram (EEG) effects of opioids, with emphasis on biophase... Show moreThe objective of this thesis was the development of a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the electro-encephalogram (EEG) effects of opioids, with emphasis on biophase distribution and target interaction kinetics. Several in vitro and in vivo studies have been performed to characterize the transport to the site of action in the brain, the receptor interaction and EEG effects. From the transport studies it could be concluded that the efflux transporter P-glycoprotein is involved in the transport of morphine, whereas for the other opioids no interaction could be identified, which was mainly due to the high passive permeability. Population modeling showed that the predicted morphine biophase concentration-time profiles in vivo were distinctly different from the brain ECF concentration-time profiles, as estimated by intracerebral microdialysis. In addition, for morphine, a complex biophase distribution model was required to describe the hysteresis between blood concentration and EEG effect whereas for the other opioids a simple one-compartment distribution model was sufficient. Investigation of the role of target interaction showed that based on the correlation between in vitro and in vivo receptor binding characteristics, two subpopulations existed. In conclusion, for the development of a predictive PK-PD model, the underlying processes should be investigated in great detail and supportive data are essential for model validation and prediction. Show less
