Reversible
Simple Direct Effects
Note, that the direct effects can be either rapid or slow.
To use this type of model, a requirement is that there is rapid equilibrium obtained between plasma drug concentrations and biophase concentrations. In other words, the max effects are predicted to occur almost simultaneously with peak drug concentrations. However, in vivo, there is generally a lag behind drug concentrations. This causes a hysteresis effect when plotting exposure versus response. If you tracked the data points in time on the exposure versus response plot, they would increase on a particular profile and then as the data points return back to the origin, they will be lower than earlier.
Note, however, that these models are only valid when the effect is either less than 20% (linear) or within 20 to 80% (log-linear) of Emax.
Also, the log-linear model breaks down when drug concentrations are less than the apparent intercept.
This is why the Hill equation came about.
koff/kon = KD
Generally, if the gamma value is >5, the gamma value is still set to 5 for modelling purposes.
Basic and Extended Indirect Effects
Precursor-dependent indirect response model
An example of this is the target-mediated PK-PD model developed for interferon-Beta1a in monkeys. The model includes receptor binding as a key factor in both PK an dPD processes and utilizes a precursor-dependent indirect response model to capture the induction of neopterin which is a classic biomarker of IFbeta receptor agonism.
Biophase Distribution
k1e and ke0 are usually set equal to each other because they are unidentifiable.
Plasma concentration changes due to this effect are considered negligible and are thus not shown in the PK.
This type of model is commonly used to account for delays in drug response.
Slow Receptor-binding
Signal Transduction
Irreversible
A few examples of irreversible drug effects are:
chemotherapy
enzyme inactivation
some certain types of toxicities
Cell proliferation model with cycle-specific inactivation
(1-R/Rss) => the upper limit of Rss
kg is the first-order growth rate constant that is the difference between the true natural growth rate and degradation.
Turnover Model
Another representation for the turnover model is as follows:
Enzyme Inactivation
No further comments at this time.
Signal Transduction
No further comments at this time.
Tolerance
Counter-regulation
Desensitization
Up- or Down-regulation
No further comments at this time.
Precursor Pool Depletion
No further comments at this time.
Misc.
It appears allometry is done with PK parameters and not so with PD and PD is assumed to be the same across-species when required.
Allometry
It appears allometry is done with PK parameters and not so with PD and PD is assumed to be the same across-species when required.
