Effect-concentration state space for the indirect link model

Numerous applications of pharmacokinetic-dynamic models incorporating a biophase (or effect) compartment for a variety of drugs that belong to miscellaneous pharmacological classes, e.g., anesthetic agents [419], opioid analgesics [420-422], barbiturates [423,424], benzodiazepines [425], antiarrhyth-mics [426], have been published. The reader can refer to a handbook [427] or recent reviews [405] for a complete list of the applications of the biophase distribution model. 

In actual practice, nonlinear regression is used to fit a suitable pharmacokinetic model described by the function c (t) to time—concentration data. Then, the estimated parameters are used as constants in the pharmacodynamic model to estimate the pharmacodynamic parameters. Alternatively, simultaneous fitting of the model to the concentration-effect—time data can be performed. This is recommended as c (t) and E (t) time courses are simultaneously observed. 

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