Pharmacokinetic and pharmacodynamic modeling of drugs and their effects continue to evolve. de Lange, Peter Bonate, in Handbook of Behavioral Neuroscience, 2019 VIII Summary An example of the application of intracerebral microdialysis is the investigations on the PK/PD correlation of morphine, where P-glycoprotein and possibly other transporters restrict distribution into the central nervous system. A novel technique for obtaining information on target site exposure in the central nervous system is intracerebral microdialysis.
16 For drugs acting in the central nervous system measures of target exposure can be indispensable in PK/PD modeling. 3 Recently several specific transporters have been discovered which may restrict the access of a drug to the site of action. This especially concerns drugs with an intracellular target (e.g., cytostatic drugs) and drugs that act in tissues which are protected by specific barriers (e.g., the central nervous system). Particularly for relatively large hydrophilic molecules and for compounds that are substrates for specific transporters distribution to the target site be restricted. 15 However, although for many drugs the assumption that in steady state the drug concentration in the effect compartment is identical to the (free) plasma concentration is plausible, this may not always be the case. The model has also been successfully applied in preclinical studies to derive meaningful in vivo drug concentration–effect relationships.
The effect compartment model has been shown to be highly useful in describing delayed drug effects owing to distributional processes. In this manner it is inherently assumed that in steady state the drug concentration in the biophase is identical to the (free) plasma concentration. Furthermore, for reasons of identifiability, the values of k 1e and k e0 are usually set equal to each other. In this model the amount of drug entering the effect compartment is considered to be negligible and therefore not reflected in the pharmacokinetics of the drug. Where k 1e and k e0 are the first-order rate constants distribution into and out of the hypothetical effect compartment and C p and C e are the drug concentrations in plasma and the hypothetical effect compartment, respectively. Let us consider how such methods can be applied to the previously described model. In the field of immunooncology, models of tumor–immune interactions could provide very useful tools for evaluating the pharmacodynamic effects of immunotherapy from a mechanistic point of view.
Once the drug has reached the site of action and has been able to interact with the target, its therapeutic effects can be evaluated. Numerous specific examples are available in the literature, see for instance. The corresponding pharmacokinetic parameters (rates of absorption, elimination, volumes of distribution, etc.) are then estimated from the obtained data, often using very well-developed software, such as WinNonlin.ĭetailed explanations of various aspects of PKPD modeling and the science behind it can be found in Ref. This is typically done through PK studies, where drug concentrations are measured at multiple time intervals after administration. īecause of all these forces acting on the therapeutic agent once it has been administered, it is important to evaluate the pharmacokinetic properties of the drug to estimate how much drug is available at the site of action at each moment. (3.2) d D periphery d t = administration − absorption − elimination, d D site of action d t = absorption − binding to target + release from target − elimination.