Separation of PK and PD
Just catching up with my reading, I've always been a fan of compounds with slow off-rates and the impact on duration of action.
The situation was elegantly summarised in a publication from earlier in the year from Copeland et al. DOI
A dominant assumption in pharmacology throughout the 20th century has been that in vivo target occupancy-and attendant pharmacodynamics-depends on the systemic concentration of drug relative to the equilibrium dissociation constant for the drug-target complex. In turn, the duration of pharmacodynamics is temporally linked to the systemic pharmacokinetics of the drug. Yet, there are many examples of drugs for which pharmacodynamic effect endures long after the systemic concentration of a drug has waned to (equilibrium) insignificant levels. To reconcile such data, the drug-target residence time model was formulated, positing that it is the lifetime (or residence time) of the binary drug-target complex, and not its equilibrium affinity per se, that determines the extent and duration of drug pharmacodynamics.
I've added it to the page on separation of PK and PD in the Drug Discovery Resources