The well accepted “free drug hypothesis” for small molecule drugs assumes that only the free (unbound) drug concentration at the therapeutic target is able to elicit pharmacological effect.  Unbound (free) drug concentrations in plasma are readily measurable and are often used as surrogates for the drug concentrations at the site of pharmacological action in PKPD analysis and clinical dose projection in drug discovery.  Furthermore, for permeable compounds at pharmacokinetic steady-state, the tissue free drug concentration is likely a close approximation of that in plasma. However, several factors can create and maintain dis-equilibrium between the free drug concentration in plasma and tissue leading to free drug concentration asymmetry.  These factors include drug uptake and extrusion mechanisms involving uptake and efflux drug transporters, intracellular biotransformation of prodrugs, membrane receptor-mediated uptake of antibody-drug conjugates, pH gradients, unique distribution properties (covalent binders, nanoparticles), and local drug delivery (e.g. inhalation).  This presentation will focus on situations in which tissue free drug concentrations may be different from those in plasma (e.g. K<sub>p,uu</sub> &gt; or &lt;1) and discuss the limitations of the surrogate approach of using plasma free drug concentration to predict tissue free drug concentrations. This is an important consideration for novel therapeutic modalities since systemic exposure as a driver of pharmacological effects may provide limited value in guiding compound optimization, selection, and advancement. Ultimately, a deeper understanding of the relationship between free drug concentrations in plasma and tissues is needed.

Drug concentration asymmetry in tissues and plasma for small molecule-related therapeutic modalities

ACS Fall 2021

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