From single-drug pharmacokinetics and pharmacodynamics to multi-drug interaction modeling: using population-based modeling to increase accuracy of anesthetic drug titration: "Surfing the wave"

This thesis describes two important aspects of mathematical modeling for anesthetic drugs. The first part is about the development of a mathematical model which describes how dexmedetomidine, a sedative drug, acts in the body. The model describes not only the changes in concentrations of the drug in the blood with time (‘pharmacokinetics’), but also the effects of the drug on sedation and on the blood circulation – blood pressure and heart rate – (‘pharmacodynamics’). This is the first model that describes the pharmacodynamics of dexmedetomidine, and also unique in investigating the combined effect on sedation and blood circulation. This enables optimization of drug administration and titration: reaching the desired effect (sedation), with the least side effects (blood pressure and heart rate).

The second part describes the influence two or more anesthetic drugs (sedatives and strong painkillers) have on each other, or drug interaction. This interaction can be on a pharmacokinetic level, where one drug influences the blood concentration of another drug, or on the pharmacodynamic level, where the drugs influence the effect – beneficial or side effect – of the other drugs. An existing interaction parameter was also redefined based on these models, which may provide the anesthesiologist with more information on the depth of anesthesia than current parameters.

Both types of mathematical models (single drug models or multiple drug interaction models) can be used to improve administration of anesthetic drugs, resulting in more stable anesthesia and easier titration, lowering the risk of over- and/or underdosing.