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Navigating DMPK: The Answers That Move Programs Forward
Mike Templin discusses using DMPK to reduce risk and strengthen drug development strategy
Mike Templin, Senior Director of Scientific Advisory Services at Charles River, recently discussed the importance of strategic ADME and DMPK data generation throughout drug development with Big4Bio for our Catalyst Conversations Podcast.
Big4Bio (B4B): Why is DMPK so important and how is it integrated into discovery and translational strategies?
Mike Templin (MT): Essentially, DMPK is an overarching science essential in drug development. ADME addresses two specific questions – can you get the right amount of drug to the correct place, and will it last for enough time to be effective? You can also think of ADME in light of how much of a drug is absorbed, where it is distributed within the body, and how it is eliminated from the body.
ADME asks the questions, and then DMPK is the overarching science that uses the information to evaluate and predict a drug’s potential for success. The questions, answers, and DMPK efforts need to be answered at the right stage and use the right approach to produce an effective and safe drug.
B4B: How does the focus and requirements for DMPK assessment evolve from discovery through late-stage development?
MT: They are essential at every step, but the questions are different depending on where you're at in the development pathway. We all start with the idea of what will make a successful drug. In addition to the pharmacological effect, key ADME processes, including absorption and metabolic stability, need to be considered. These characteristics can provide basic information on exposure and flag potential efficacy and toxicity risks. You need to ask and answer those questions early. Later in the process, you'll ask questions about absorption or exposure profiles. What is the best regimen to take the drug? What is the best dose in order for it to be effective? A key point is to identify what makes a good candidate, and then later focus on how you should best use your lead candidate or final drug candidate.
So, the types of studies are based upon the goals and current status. It's not that they get more complex; it has to do more with building on pieces of information and asking more dynamic questions. Ultimately, we start with: What are our assumptions? What is our best guess? What are our estimates for a dose that's going to be effective in humans? It’s a high number of data points that go into these later steps. It’s a building process – things don’t get more or less complex as you move along the pathway.
B4B: How do you integrate DMPK findings with toxicological data to build a comprehensive picture of a compound's safety and pharmacological behavior?
MT: It all comes down to exposure. That is, how much drug is in the blood, or more often how much drug is in a certain tissue. So, toxicology is always the question about the dose and response, like a maximum tolerated dose, or what is a safe dose. Toxicology is looking at the exposure profile in the system we're studying – whether in vitro, in an organoid system, or in an in vivo model.
You then use that information to determine what concentrations of the molecule were well tolerated in a compartment of interest (e.g., blood) and above what concentrations it was not tolerated. This gives us the essential information on the potential negative consequences, and we balance that with information on what concentration the drug was beneficial. Of course, in a perfect world, the concentration at which you have benefit versus the concentration that raises concern (the so-called therapeutic index) is a very wide margin. Sometimes that value gets relatively narrow, and the exposure information becomes essential to say, is my therapeutic index, my margin of safety, still viable for a marketed drug?
B4B: What are some common oversights or pitfalls sponsors encounter when planning DMPK studies?
MT: Probably the most common miscalculation is the idea that you can fix it later. It's very difficult to fix things later. If you compromise your criteria, if you compromise your set points for a go/no-go decision, it always becomes more difficult to change in the end, and resources that could have been spent on a drug candidate that was more appropriate may be wasted.
Another is overlooking the fact that there are multiple data points when it comes to DMPK, and in the speed of drug development it is tempting to minimize time and effort to generate and analyze the necessary data. How quickly is it absorbed? Is it metabolized? Is there a metabolite-related toxicity risk? How is a drug candidate eliminated and how fast? Could a safe and effective dosing regimen be achieved?
It may be tempting to settle for a “good enough” outcome and progress through the steps, but as the project matures, smaller misses add up. Based on early ADME data, however, it is possible to modify the candidate in time to avoid major pitfalls later.”
Michael V. Templin, PhD, DABT, Senior Director of Scientific Advisory Services
B4B: Beyond scientific insights, how may DMPK data guide business and strategic decisions?
MT: Well, we all know good science underlies drug development, but ultimately we're trying to create a commercial entity. Almost all drugs out there will have competitor drugs, and we all want our candidate to be better than its competitor. However, we need to be realistic about positives. DMPK and ADME provide essential information on dose, dosing schedule, and potential benefit. It is also important not to lose sight of the potential negative differences, or you may end up with a drug that may be a very effective drug, but also inconvenient for a patient. Again, you must ask and answer these questions early because mending things later can be very challenging.
B4B: With such complex studies and strategies that evolve with the development process, are there any standard strategies developers can follow to avoid later complications?
MT: Indeed, there are standard questions, and there are standard processes that are in place. But the risk of relying mostly on standards is that we may neglect context-specific questions. There are plenty of publications that one can reference for planning their program: find a similar molecule, see how it was developed, what the key questions were, and how the data to answer them were generated and interpreted. So, in a way, we can consider this quite standardized. Let’s not forget, however, that each drug is a unique entity that will be used in a specific patient population with certain considerations.
Standardization is more of a reference, and you should always leverage preexisting information for specific considerations. The ideal program is a combination of using what's available and effectively applying the knowledge but not losing site of what and why a program is unique.”
B4B: Are there any specific tricks for adapting DMPK strategies for newer therapeutic classes?
MT: The high-level questions are the same. Again, trying to understand how the body will process the drug. How is it administered? Where's it going to go? How long is it going to be there? Are you going to have an effective concentration? It's just that each of those modalities has its own unique characteristics and how they will interact with a biologic system.
But it always comes down to exposure and finding the levels that provide pharmacologic benefit, and the levels where risks may arise. You're still asking the question about how the body processes this. It's just that you have to ask and answer the questions in different types of studies and in different ways.
B4B: Finally, how does your team integrate DMPK with discovery automation and translational strategy?
MT: I'll use a toolbox analogy, meaning that Charles River has a significant number of tools that can be used in the process of drug development and a significant number of individual assays. It is critical to choose the right tools needed to develop a certain drug: which tool, what setup, what output to generate, and how to interpret it. We not only have many options, but we also have a large number of drug development professionals who know how to best leverage them to support the very complex process of drug development.