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Indirect Link PK/PD Model

Now there is an indirect link PK/PD model because many protein drugs actually do not fit the direct link model. Why is that? Because there is a distributional delay of the concentrations between the plasma and the effect site for the biologics. That is the effect lags behind plasma concentration, and therefore plasma concentration actually peaks before effect maximum.
The response curve follows a counter-clockwise hysteresis. But remember the effect is still mediated via the interaction of the biologics and the receptor. Let’s look at the sketch for the indirect link PK/PD model. Here the drug is injected into the central compartment. The drug in the central compartment or the biologics equilibrated with the effect compartment, which is in equilibrium between the effective compartment and the effect site. And, therefore, the relationship between the effect and the concentration at the effect site is directly linked. However, there’s an indirect link between the plasma concentration and the effective compartment because of the distributional delay of the biologics. Let’s just look at another example quickly. This is not a biologic protein, it’s a small molecule.
Nevertheless, it illustrates the indirect link pharmacokinetic model. The plasma concentration and their response. So here, the plasma concentration peaks at about one hour. But effect does not peak until about five, six hours later. And that is because of the distributional delay of the concentrations between the plasma and the effect site. So when you look at the plasma concentration, it peaks earlier. As you compare to the pain reduction, which peaks later. But if you simulate tissue concentration or the concentration at the effect component, then the peak times are consistent with each other between the tissue concentration and pain reduction.

Direct link model is the most straight forward if there is no time delay between the plasma concentration and the response. However, this is not the case with most biologics. The indirect link model stipulates a separate effect site outside the central compartment, and the drug distribution to that compartment causes the delay of effect. Since no biologic example is available, diclofenac, a non-steroid anti- inflammatory is used to model the pain intensity response. When the effect compartment concentration is simulated from the plasma profile, the response is shown to directly correlated with the tissue (effect site) concentration.

The indirect link model differs from the direct link model by a separate, distinctive, effect compartment, as shown in the sketch The model assumes that drug concentration distributes to the effect site with a time delay, after which the drug concentrations between the tissue compartment and the central compartment are equilibrated. The delayed response is directly elicited by the drug concentration at the effect site, whose concentration is in equilibrium with the plasma compartment. By deduction, if an indirect model is observed, a distinctive effect compartment, a distribution lag and delayed response are implied.

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Pharmacotherapy: Understanding Biotechnology Products

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