This is a must-read paper for anyone who is involved in the drug discovery or drug development processes. It is one of the most referenced papers by DDS because it reinforces a key principle in modern DMPK: The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery by Dennis A. Smith, Li Di, and Edward H. Kerns.
It’s an excellent read and a valuable reminder that DMPK calculations, PK/PD interpretation, and dose projections should be focused on unbound concentrations rather than total levels. The authors make a strong case that in vivo efficacy is driven by the free (unbound) drug concentration at the target site, not the total plasma concentration or protein binding percentage alone.