Free Drug Hypothesis in Drug Discovery and Clinical Pharmacotherapy

Do we know why understanding the nuances associated with the free drug hypothesis is important for both drug discovery and clinical pharmacotherapy?

Free drug hypothesis defines that (1) changes in drug action (pharmacodynamic or PD) is associated with changes in unbound drug concentration at target tissue (CuT), and (2) based on passive diffusion theory, CuT is equal to unbound drug concentration in plasma (Cu). This means that the ratio of CuT to Cu (Kpuu) is equal to 1 at pharmacokinetic (PK) steady-state (e.g. fluconazole). Consequently, Cu is a relevant framework for PKPD and dose prediction.

However, there are instances when Kpuu < 1 or >1. Here, Cu is not a good predictive surrogate of CuT.

Kpuu < 1

1. Drug is rapidly cleared by metabolism or efflux transport in the tissue (e.g. eliquis in brain)

Kpuu > 1

1. Active uptake of drug is greater than efflux and other elimination mechanisms in the tissue (e.g. statins)
2. Lysosomal trapping of drug (e.g. garenoxacin)
3. Covalent binding drug (e.g. afatinib)
4. Prodrug that forms active drug in tissue (e.g. tenofovir)
5. Antigen-mediated uptake of antibody-drug conjugate (e.g. kadcyla)
6. Unique distribution properties of nucleic acid drugs (e.g. fomivirsen)

In summary, when the free drug concentration in tissues (CuT) cannot be measured or easily extrapolated from that in plasma (Cu), the plasma exposures (AUC∞) may have limited utility in guiding candidate selection or compound advancement because plasma exposures cannot be related to effect for PK/PD modeling and human dose projection. For these therapeutic modalities, in vitro-in vivo extrapolation (IVIVE) to predict tissue concentrations warrants further development.

Read also:

• Effective Design of Clinical Trials | FDA
• Different Types of Clinical Research Studies

Resource Person: Eric Chan, PhD