Indirect response (turnover) models
An indirect response model describes an effect that arises when a drug changes the production or loss of a response variable that turns over in the body, so the effect lags behind the plasma concentration.
Definition
In an indirect response model the drug does not produce the effect directly. It inhibits or stimulates the production, or the loss, of a response variable that is continually produced and lost (turns over), for example a clotting factor. The response variable's level follows the drug through its own turnover, so the effect lags behind the concentration.
Four basic types
The drug can (1) inhibit production, (2) inhibit loss, (3) stimulate production or (4) stimulate loss, usually through an Emax or Hill function of the concentration (Dayneka, Garg and Jusko, 1993).
Why it matters
Plasma concentration and effect are not in step. Peak effect comes after the peak concentration, and a short exposure can have a long effect. Fitting a direct Emax model to such data distorts the parameters.
On this site
The warfarin PK/PD analysis uses a turnover-type response in which the turnover rate delays the response even when the plasma concentration changes promptly. The degrader analysis links a drug's PK to its effect on the target protein level through turnover, and asks whether maximal degradation alone can set the dosing interval.
Frequently asked questions
Why does the effect peak after the plasma concentration?
The response variable must change through its own production and loss, so the drug effect on its level builds up gradually.
Which of the four types applies to warfarin?
Warfarin reduces the synthesis of vitamin K-dependent clotting factors, which is an inhibition of production.