Free drug theory (FDT) is like a dogma for the analysis of in vivo pharmacokinetics and pharmacodynamics (PK/PD).^{1),2),3),4),5)} Drug-like small molecules tend to be bound to plasma and tissue proteins and lipids and only a fraction of the administrated molecules is in the unbound state. The issue of free concentration of drug and its asymmetry in our body need to be considered in defining drug dosing regimens.⁶⁾ Extrapolation of readily measurable plasma concentration of whole bound and unbound drug molecules to tissue concentration is also a significant issue to solve even in the early drug development stage.⁷⁾ Here we would take a look at the myth of FDT and its importance along same context.

FDT states freed drug concentration in plasma is equal to free drug concentration in tissue after equilibrium has attained, and the free drug in the tissue only binds to the target protein or other class of biomolecules to exert the pharmacological effect.

This hypothesis is well-accepted in pharmaceutical science because the concept is readily understandable. Free-form drug in plasma passively diffuse to the tissues in its native form and bind to the target. But the bound drug cannot get into the tissues because of the difficulty of dragging the bound macromolecule through the cell membrane.

The common drug binding blood proteins are human serum albumin, lipoproteins, glycoproteins, and globulins. Clinical relevance of the drug bindings has been investigated and it was revealed that the free drug concentration can change easily by the patients’ conditions.⁸⁾

But there are several different viewpoints in the importance of free drug concentrations. For example, there is an opinion that total exposure has more significance rather than individual PK parameters.⁹⁾ It is also indicated that high plasma protein binding (PPB) becomes an unignorable issue when more than 70% are bound to the plasma proteins. But it is necessary to keep it in mind because most of the small molecule drugs with lipophilic nature tend to have around 90% binding in plasma.

FDT is a basis for surrogating and estimating the real and effective concentration of the drug according to the whole plasma concentration. Unbound concentration is measurable to determine the free portion of the administered drug molecule. But the concentration of really active drug in the target issue is obscure and it is crucial to optimize the regimen even after the approval.

The impact of free concentration needs to be assessed when a candidate is thrown into the clinical trial. It thoroughly depends on the target and approach. It is possible that the program is not standing the stage where FDT does not work. New modalities have different importance of FDT and it need to be considered when start a new program for any drug discovery and development.

1. https://doi.org/10.1002/jps.23614
2. https://doi.org/10.1067/mcp.2002.121829
3. https://doi.org/10.1038/nrd3287
4. https://doi.org/10.1021/jm5007935
5. https://doi.org/10.1016/j.xphs.2017.09.005
6. https://doi.org/10.1016%2Fj.xphs.2021.05.018
7. https://doi.org/10.1124/dmd.119.086744
8. https://doi.org/10.1007/s40262-012-0018-5
9. https://doi.org/10.1067/mcp.2002.121829