Free drug theory

ALAN TALEVI; CAROLINA L. BELLERA

The ADME Encyclopedia. A Comprehensive Guide on Biopharmacy and Pharmacokinetics

Springer Nature

Año: 2022; p. 492 - 497

The free drug theory (sometimes also termed free drug hypothesis) provides a conceptual framework increasingly used to understand pharmacokinetics/pharmacodynamics (PK/PD) relationships [1]. It underlines the central role of free (or unbound) drug concentration at the site of action (the surroundings of the drug target) as determinant of in vivo efficacy and pharmacokinetics. A deep understanding of this theory can also be helpful to establish in vitro-in vivo correlations, or, alternatively, to provide explanations to lack of correlations between in vitro and in vivo studies.The free drug theory can be enunciated in two parts [2]. The free drug theory part I states that, at steady state, the unbound drug concentration will be the same on both sides of a biological membrane. Provided that some requisites are verified, thus, the free drug concentration will be the same in plasma, extracellular fluid, and intracellular fluid. The free drug theory part II states that it is the unbound drug concentration at the site of action of the drug (and not the total drug concentration, bound and unbound) the one that determines the biological activity / response, as only the free drug in the tissues is available to engage its intended target (and, more generally, any other binding partner). Table 1 presents an in vitro potency measure and the in vivo unbound drug concentration for a list of drugs. IC50 denotes the half-maximal inhibitory concentration, that is, the concentration of inhibitor required to reach 50% inhibition under given experimental conditions (depending on the inhibitory mechanism, it may vary, for instance, with the substrate concentration in the assay). Ki is the inhibition constant, which reflects the potency of target inhibition. The standard approach to determine this constant is time-consuming, as it consists in incubating varying concentrations of the substrate (around the Km) and inhibitor (around the Ki) with fixed amounts of the target, for a constant time period. Kb symbolizes the equilibrium binding constant, a measure of drug potency in a receptor binding assay. While IC50 reflects the functional strength of an inhibitor, the inhibitor and binding constants reflect the affinity of the drugs for their target. Note that whereas the in vitro and in vivo values in the table are not strictly identical, they are within the same order of magnitude. Bearing in mind that the in vivo concentrations reported in the table are just average free drug concentration and that, at has already been mentioned, IC50 may be highly dependent on the experimental conditions, the drugs in Table 1 represent examples of good correlations between in vitro potency and in vivo unbound drug concentrations at the mean efficacious dose.