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Biochem wolfram systemmodeler9/11/2023 ![]() Now, with the TMDD model, we could actually turn directly to the question at hand and search for the dose giving us our 10% TO. Further, the PD of the mAb is described by the target synthesis, degradation, and target-mAb binding reactions. In principle, numerous approaches exist for building PK/PD models, but in this example, we’ll make use of a target-mediated drug disposition (TMDD) model, which is a type of model frequently used to describe the PK/PD of mAbs.īy using components from the BioChem library, we can easily put together the TMDD model in SystemModeler and get something looking like this:įrom the diagram, we can decipher that the model describes mAb PK by 1) a user-specified input describing the rate of appearance of the mAb in blood plasma, 2) a tissue compartment to describe non-specific mAb tissue binding or distribution, and 3) two possible mechanisms for mAb elimination: either by direct elimination or by target binding and subsequent degradation. the relationship between the drug’s concentration and its effect on interesting biomarkers). the absorption, distribution, and elimination of the drug), and the PD means that the model also describes the pharmacodynamics of the drug (i.e. In pharmacology, such a model is usually referred to as a PK/PD model, where the PK means that the model describes the pharmacokinetics of the drug (i.e. The first thing we need to do is build a model that somehow relates the mAb dose to our biomarker. OK, so let’s begin with the task at hand. The Target Mediated Drug Disposition Model ![]() This is a question we should now try to answer using modeling and simulation. To define our MABEL, we can say that we, for example, want no more than 10% TO in our first trial, and finding a recommended starting dose is then a question of finding a dose that would give us the 10% TO. The most sensitive biomarker is then typically the target occupancy (TO), that is, the relative number of target molecules bound by the mAb. For instance, let’s say that our mAb works by binding to and neutralizing a certain type of target molecule-a common mechanism of action of mAbs. The MABEL is usually defined by 1) looking at the most sensitive biomarker associated with the drug’s mechanism of action, and 2) specifying how much this biomarker is allowed to change. The EMEA proposes that we should use a trial-starting dose that will result in the minimum anticipated biological effect level (MABEL). Second, let’s hypothesize that we have developed a new type of therapeutic mAb that we want to test in a clinical trial. Due to their very specific nature and long half-lives, selecting starting doses for mAbs can be tricky, and tools that can aid this process are of added importance. To make things a bit easier to follow, let’s set up an example.įirst, to keep things focused, we’ll limit the example to mAbs. The Minimum Anticipated Biological Effect Level Interestingly, the guidelines recommend that the use of modeling and simulation should play an integral part in the selection process, and in this post I thought we would study what such an approach might look like using Wolfram SystemModeler and Mathematica. However, as a consequence of the dramatic happenings in 2006, the European Medicines Agency (EMEA) recently published new guidelines to address the issue of starting dose selection in first-in-human trials. It’s also beyond the scope of this blog post. Now, as you may guess, the complete answer to this question is not an easy one. The tragic event shocked the medical community and highlighted a very important issue: how do you select a safe starting dose in first-in-human trials? Although the trial was run according to an approved protocol, all volunteers receiving the drug had severe inflammatory reactions and multiple organ failure. In 2006, a first-in-human clinical trial of an mAb, aimed at treating leukemia and rheumatoid arthritis, went terribly wrong. The history of mAbs has, however, not been without problems. Today, more than 30 different mAbs are successfully used in the clinic-playing important roles in treating complex diseases such as cancers and auto-immune disorders-and more than 200 are in clinical trials. During the last decades, the development and use of therapeutic monoclonal antibodies (mAbs) have grown rapidly. Explore the contents of this article with a free Wolfram SystemModeler trial.
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