Pharmacodynamics effect-compartment

Jusko, W.J. Conceptualization of drug distribution to a hypothetical pharmacodynamic effect compartment. Clin. Pharmacol. Then 1993, 54, 112-113. 

Lin, S. and Ghien, Y.W., Pharmacokinetic-pharmacodynamic modeling of insulin comparison of indirect pharmacodjmamic response with effect-compartment link models, J. Pharm. Pharmacol, 54, 791-800, 2002. 

The treatment of the data proceeds as a two step procedure. First, a suitable PK model is fitted to the concentration-time data. Then a PD model is fitted to the data as described by the PK model, simultaneously solving for pharmacodynamic parameters (e.g. max. 50% s) and the effect compartment parameter eO-... 

A mechanism-based PK/PD model for rHu-EPO was used to capture the physiological knowledge of the biological system. An open, two-compartment disposition model with parallel linear and nonlinear clearance, and endogenous EPO at baseline, was used to describe recombinant human erythropoietin (rHu-EPO) disposition after intravenous administration [35]. The pharmacodynamic effect of rHu-... 

During the first decades of the development of pharmacokinetic science, a lag time in pharmacological response after intravenous administration was often treated by applying a compartmental approach. If the plasma concentration declined in a biexponential manner, the observed pharmacodynamic effect was fitted to plasma or tissue compartment concentrations. Due to the lag time of effects, a successful fit was sometimes obtained between effect and tissue drug level [414]. However, there is no a priori reason to assume that the time course of a drug concentration at the effect site must be related to the kinetics in tissues that mainly cause the multiexponential behavior of the plasma time-concentration course. A lag time between drug levels and dynamic effects can also occur for drugs described by a one-compartment model. 

Population pharmacokinetics can be extended to pharmacodynamics and PK/PD modeling using a link model like an effect compartment (Sheiner et al. 1979). In huge clinical trials only a limited number of patients can be included in a pharmacokinetic satellite study. The model is developed in this satellite. Knowing the demographic covariates of the patients in the whole study, concentration time curves and even effect time curves can be predicted. 

Holford NHG. Physiological alternatives to the effect compartment model. In D Argenio DZ, editor. Advanced methods of pharmacokinetic and pharmacodynamic systems analysis. New York Plenum Press 1991. p.55-68. 

The relationships between antibody dose, antibody affinity (or catalytic antibody K,.j. and their effects on the drug s pharmacokinetics and pharmacodynamics are poorly understood. For instance, if the drug effect compartment is associated with the pharmacokinetic peripheral compartment, the time needed to reverse drug effects with antibodies would be predicted to be slower than if the effect compartment is associated with the pharmacokinetic central compartment. In addition, it appears that high-affmity antibodies block the metabolism and/or change the metabolic profile of drugs (Owens and Mayersohn 1986 Valentine et al. 1994). These are complex changes that need to be studied in detail, and pharmacokinetic and pharmacodynamic models of these effects need to be developed in animal models before use in humans. 

Equilibrium as well as rate constants are related to free energy values AG by relationships of the type of eq. 11 (cliapter 1.2). Thus, only equilibrium constants (e.g. K values or at least IC50 values, not % inhibition at a certain concentration) and rate constants (e.g. log k values, not % absorption or % concentration in a certain compartment) are suited for QSAR studies, which means that all biological data have to be transformed in an appropriate manner before being used in quantitative analyses. In the case of complex biological data resulting from a sequence of several independent processes (in the worst case whole animal data), sometimes one effect predominates e.g. the bioavailability, the penetration of the blood-brain barrier, or the affinity to the receptor site. In other cases several effects overlap, which makes the QSAR analysis much more difficult. Due to the nonlinear characteristics of dose-response relationships, % effect values at a certain dose must not be used in QSAR equations. In each case they have to be transformed to equieffective molar doses (i.e. dose levels which produce or prevent a certain pharmacodynamic effect dose levels that increase the life span of animals to a certain extent dose levels which kill a certain percentage of the animals). 

Pharmacokinetic/pharmacodynamic model using nonlinear, mixed-effects model in two compartment, best described time course of concentration strong correlation with creatinine clearance predicted concentration at the efi ect site and in reduction of heart rate during atrial fibrillation using population kinetic approach... 

The optimal administration of drugs in clinical practice is facilitated by effective application of the principles of clinical pharmacokinetics (PK) and pharmacodynamics (PD). Relationships between drug levels in the systemic circulation and various body compartments (e.g., tissues and biophase) following drug administration depend on factors governing drug absorption, distribution, elimination, and excretion (ADME). Collectively, the study of the factors that govern the ADME processes is termed pharmacokinetics. 

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