Pharmacokinetics and the drug–target residence time concept

• Combined effect of pharmaco- and binding kinetics on duration is investigated.
• Dissociation will only affect duration of binding when slower than the elimination.
• For several marketed drugs the opposite is true; elimination is slower.
• These findings greatly reduce the use of drug–target residence times.
• Important to avoid kinetic generalizations and simplifications.

The concept of drug–target residence time has been in focus in recent drug discovery literature. However, few studies consider the combined effect of pharmacokinetics (PK) and binding kinetics (BK) on the duration of effect of a drug. Using a simple model that takes both PK and BK into account, we found that prolongation of binding owing to a long drug–target residence time can only occur when the binding dissociation is slower than the PK elimination. Data for several drugs and/or drug candidates in the literature indicate that the opposite is observed, that is, they have a slower elimination compared with dissociation. These observations greatly reduce the usability of drug–target residence times for estimating the duration of effect of a drug in vivo.