Introduction to Apocalyptic Clinical Pharmacology in Drug Development

Introduction to Apocalyptic Clinical Pharmacology in Drug Development

In this blog, I will introduce “apocalyptic clinical pharmacology” and provide a framework for using this approach in drug development, which can save resources and time. Apocalyptic clinical pharmacology in drug development provides value offering a framework for thinking about the relationship between the drug dose and the biological system.

What is apocalyptic clinical pharmacology?

Usually “apocalyptic” is associated with a dramatic end to something or used to imply a dramatic effect. But to understand this word in drug development, one needs to look at the Greek word apokalypsis, which apocalyptic is derived from. There are two parts to the word: apo, which means away or off, and kaluptein, which means to hide. When these parts are combined the result is to remove something that’s hidden or to reveal something.

How would revealing something be related to the drug development process? During this process, pharmaceutical companies go through many steps from preclinical development to clinical trial phases to marketing and commercial use. Throughout these steps, the drug itself stays the same (ie, no changes are made to the molecule). But, at each step information is revealed about the drug that contributes to the understanding of how the drug works and under what conditions its activity is optimized. This information not only helps in investment decisions during drug development but is essential at the regulatory approval stage too.

Synthesizing two ideas together creates the basis of apocalyptic clinical pharmacology: an appreciation of drug features, system features, and uncovering the interplay between the two. The interaction of the drug with the system (and vice versa) is fixed by the 3D structure of the molecule, whether it’s small or large, the chemistry of the drug, and the biological system in which it is placed.

Adoption of this “revealing” mindset is advantageous for drug developers seeking regulatory approval because it provides the framework for understanding the interaction of the drug with the system and for answering the questions of regulatory authorities who are evaluating the safety and efficacy of the drug. Such an approach arms pharmaceutical companies with the knowledge about their drug to make informed decisions throughout the drug development process. In the next section, I will explain how you apply this framework and how to perform apocalyptic clinical pharmacology.

How to perform apocalyptic pharmacology

How do pharmaceutical companies and drug developers go about unveiling the complex interactions between the drug and the system?

Each of step of drug development seeks to progressively reduce uncertainty. The amount of knowledge uncovered should be consistent with the development decisions being made. In the entire scheme of drug development, there isn’t time and resources for a purely empirical approach. Pharmaceutical companies cannot perform every possible study to uncover every detail about the relationship between the drug and the system. But, it is possible to perform key studies to determine enough information to understand relationships and then fill in the gaps with a modeling approach and predictive tools. Certara has extensive experience with using these tools to help pharmaceutical companies optimize their drug development strategy. Through this approach, drug developers understand how their drug works in the system and then can make good drug development decisions. That is the essence of apocalyptic clinical pharmacology.

Apocalyptic clinical pharmacology focuses on understanding the relationship between the drug dose and regimen and the response elicited. Other underlying relationships that support this, such as dose to pharmacokinetics and pharmacokinetics to pharmacodynamics, help to provide a nuanced understanding of the contributors to the overall dose/regimen-response relationship.

I advocate using a “begin with the end in mind” approach. Ideally, pharmaceutical companies want their drugs to progress through to submission and approval and have agreement from payers.  But, it is vital to unveil dose/regimen-responses iteratively in a stepwise manner, with strict enforcement of pre-defined drug performance hurdles at key stages in the development pathway. Each step in the unveiling process requires clarity on what needs to be known (or unveiled) and what constitutes an acceptable outcome.

How to examine relationships with apocalyptic clinical pharmacology

Imagine a virtual world of drug-system interactions. If all that could be known about the drug properties and the system properties was known in advance, the job would be complete before it started! The optimal dose and response (whether efficacy or safety) could be predicted in advance. Perhaps one day this drug development nirvana will be realized. But for now, we have to be content with uncovering just enough for each decision step. In designing development studies, there are surprisingly few variables to play with—two on the drug side and two on the system side, just four levers. The development objective is to unveil sufficient understanding of the relationships, having done so to decide to progress the development or not.

Lever 1: Dose—The relationship to response, pharmacokinetics (PK), and pharmacodynamics (PD)

All the levers are related to dose, and the first question relates to the dosing strategy. This is conceptually simple. Yet companies often do not devote sufficient effort to develop an adequate understanding of dose-response relationships. If the dose is not optimized early in development, the program may fail to get the most out of the drug (under dosing) or, in an overly optimistic effort to maximize effect, the drug may be needlessly overdosed. It’s all about adequately understanding the relationship of dose to response. And recall that underlying dose-response are the relationships of PK to dose and PK to PD.

Lever 2: Frequency of the dose

This is closely related to the first lever (what is the best dose); but what is the best frequency of dosing? How often should the drug be taken? As we understand the relationships described above, we can optimize not only the dose but the frequency of the dose.

The first two levers are on the drug side and understanding how to dose the drug. But we need to consider the system side as well. The two remaining levers relate to understanding the best dose under specific circumstances of the system into which the drug is placed.

Lever 3: Extrinsic factors/conditions

This lever relates to factors that affect the drug in the system. Some examples are the influence of food on drug absorption and the influence of co-administered drugs on drug exposure and drug response.

Lever 4: What are special considerations for populations that the drug is given to?

Clearly the patient population is the key component in this lever. What is the most appropriate patient population to potentially derive benefit from the pharmacology of the drug? Other system factors such as patient genetics (which could influence drug clearance and distribution as well as pharmacological response) are part of this picture. In any clinical pharmacology program, other features of the patient population will influence the selection of dose and dose regimen such as renal and hepatic function, ethnicity, age, and body mass.

Apocalyptic approaches help pharmaceutical companies unveil the data required to understand relationships between dose and drug-response. By adopting a judicious unveiling approach to drug development, companies can optimize their drug development programs to create efficiencies and avoid late stage failures.

To learn more about how to maximize the use of apocalyptic clinical pharmacology in drug development, please watch this webinar I presented on this topic.

Graham Scott

About the Author

Graham Scott

Independent Clinical Pharmacology Consultant

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Dr. Scott has more than 30 years’ experience in the pharmaceutical industry, having worked in various roles in pre-clinical, early clinical, and clinical pharmacology drug development. He has varied and deep experience in early clinical development, having led more than 30 FIM studies and "early-in-human" studies. He has interacted with all major health regulatory authorities, having led and overseen multiple filings. His work experience has been with top 20 pharma companies in the UK, US, and mainland Europe. Most recently, Dr. Scott led Takeda’s European clinical pharmacology team and one of their global clinical pharmacology therapeutic areas. He has completed a leadership program at INSEAD, is a member of the Royal Pharmaceutical Society, and obtained a PhD in Drug Metabolism from the University of Strathclyde.