residence time
Residence time is how long a drug actually sits on its target before letting go — the average duration of one bound encounter, like how long a guest stays at a party rather than how strongly they were invited. A drug with long residence time keeps working on a target even after its concentration in the blood has fallen.
Mathematically, residence time is the reciprocal of the dissociation rate constant (1/koff): a slower off-rate means a longer stay. It is governed by binding kinetics, not just affinity — two drugs with the same Kd can have very different residence times if they associate and dissociate at different speeds.
Long residence time can be a therapeutic advantage, sustaining target engagement and effect between doses and sometimes improving selectivity, since the drug may dwell longer on the intended target than on off-targets. But it is a double-edged sword: slow dissociation also means slow reversal if an adverse effect appears, and very tight, long-lived binding can blur into effectively irreversible inhibition.
Tiotropium, a bronchodilator, binds muscarinic receptors with a very long residence time, giving once-daily dosing even though the drug clears from plasma far faster.
Residence time, set by the off-rate, governs how long target engagement lasts.
Residence time can predict in-vivo duration of action better than Kd does, because once blood levels drop, what keeps a drug working is how slowly it leaves the target.