Analysis of pharmacokinetic-dynamic interrelations with special reference to applications in cardiovascular clinical...

The relationship between a (detectable) cardiovascular response and plasma concentrations is affected by 1. the temporal delay of the equilibrium between sampling site and effector site(s), 2. the intrinsic relationship between the primary effect(s) and concentration at the effector site(s) and 3. inter-pharmacodynamic processes that link the primary effects to a net response and that might attenuate or amplify the primary effects. Confounding factors (active metabolites, time-variant protein-binding, enantiospecific pharmacological behavior, physiological counter-regulation, etc.) might confuse the issue even more. Models that address kinetic-dynamic interrelations are usually confined to the first two processes listed above and hardly account for the third factor (and often are inadequate if more than one confounding factor is involved). They yield model-driven assimilative solutions that are characterized by a high level of indetermination. The "fit" of the experimental data with an analytical model (in itself usually quite appealing by its mathematical elegance and inductive creativity) should not be mistaken as a "match" between the model and physio-pharmacological "reality". In consequence, these models are cognitive constructions that provide important insight in the complexity of these physio-pharmacological processes without necessarily solving it. Their actual "proof" and ultimate value thus lies in their practical applicability (i.e. their effective instrumental use) to predict, correct and optimize (pharmacotherapeutic) response. Unfortunately most models have failed to be successfully tested in this regard.