Abstract

Even though significant efforts have been spent in recent years to understand and define the determinants of in vivo potency and clearance, important pieces of information are still lacking. By introducing target turnover into the reasoning, we open up to further the understanding of central factors important to the optimization of translational dose-concentration-response predictions. We describe: i) new ('open' model) expressions of the in vivo potency and efficacy parameters which embody target turnover, binding and complex kinetics, also capturing full, partial, and inverse ago­nism, and antagonism, ii) a detailed examination of 'open' models to show what potency and efficacy parameters have in common and how they differ, and, iii) a comprehensive literature review showing that target turnover rate varies with age, species, tissue/subregion, treatment, disease state, hormonal and nutritional state, and day-night cycle. The new 'open' model expression which integrates system- and drug properties, shows that: fractional turnover rates rather than the absolute target or ligand-target complex expression determine necessary drug exposure via in vivo potency; absolute ligand-target expression determines the need of drug, based on the transduction Rho and in vivo efficacy parameters; the free enzyme concentration determines clearance and maximum metabolic rate; the fractional turnover rate determines time to equilibrium between substrate, free enzyme and complex; properties of substrate, target, and complex demonstrate non-saturable metabolic behavior at equilibrium; non­linear processes previously referred to as capacity- and time-dependent kinetics may occasionally have been disequilibria; and, the 'open' model may pinpoint why some subjects differ in their demand of drug.

Significance Statement ‘Understand the target turnover’ is a central tenet in many translational dose-concentration-response predictions. New ‘open’ model expressions of in vivo potency, efficacy parameter and clearance are derived and anchored onto a comprehensive literature review showing that target turnover rate varies with age, species, tissue/subregion, treatment, disease, hormonal and nutritional state, day-night cycle, and more. Target turnover concepts will therefore significantly impact fundamental aspects of pharmacodynamics and pharmacokinetics, thereby also the basics of drug discovery, development, and optimization of clinical dosing.