Clinical pharmacology is a key part of any clinical development plan. In the context of drug development, clinical pharmacology is the study of drugs and their actions in humans, and the relationship between drug exposure and clinical effects. It enables us to understand a drug’s pharmacokinetics (PK), or the exposure and disposition of the drug in the body, and pharmacodynamics (PD), or the drug’s activity and off-target or adverse effects. In terms of a clinical development program, clinical pharmacology studies are Phase 1 studies that establish the PK and PD of a compound, as well as investigating what factors can impact drug exposure and activity, such as age, race, organ dysfunction, smoking, and other drugs a patient may be taking. Information derived from these studies guides the safe usage of a drug and makes up a significant portion of the drug label and prescribing information.

A well-designed clinical pharmacology program should provide the following information:

• Do clinical pharmacology studies provide supporting evidence of effectiveness?
• Is the dosing regimen appropriate for the general population with the disease?
• Are alternative dosing regimens or management strategies required for subpopulations based on intrinsic factors such as age, race, or organ dysfunction?
• Are there clinically relevant drug-drug or food-drug interactions? What is the appropriate management strategy?

Early planning can help ensure clinical studies capture the PK and PD data needed to support decision making as the compound progresses through clinical development. Ideally, planning for the clinical pharmacology program starts well before a new potential drug enters the clinic, with nonclinical studies conducted both in vitro and in vivo to evaluate the PK, metabolism, safety, and pharmacology of a drug candidate. Data from nonclinical studies are often used to anticipate exposure in humans, to select appropriate starting doses and anticipated therapeutic dose range, and to inform whether there are any pharmacological biomarkers that can be used to measure activity of the drug in people. Close collaboration between nonclinical and clinical pharmacology teams is vital for designing clinical pharmacology studies.

The initiating study of a clinical pharmacology program for a new potential drug, either a small molecule or a large molecule, is often conducted in healthy volunteers who are administered either single or multiple ascending doses of a drug or placebo, although there are some scenarios where patients in the targeted disease may participate in the initial first in human study. The goal of this initial study is to evaluate the safety and PK of the new molecule across a range of doses. The first in human study should also be viewed as a bridge to future clinical development plans. Once this study is complete, the clinical pharmacologist can start to develop the strategy and timing of studies for the remainder of the clinical pharmacology program in conjunction with the overall clinical development plan. Each clinical development program is unique, and clinical pharmacology studies may need to be staggered appropriately to best inform dose selection and provide dose rationale for Phase 2 and 3 studies and to mitigate risks as the compound moves into later stages. An important question to ask at the start of any clinical pharmacology program is what the objectives of the clinical program in the short and long term are, and how can clinical pharmacology studies be designed to achieve those goals.

In addition to the Phase 1 studies that comprise the clinical pharmacology plan, clinical pharmacology is integral to the design of the Phase 2 and 3 studies in terms of both the dose selection and regimen, as well as PK and PD sampling during those studies. PK and PD samples in the Phase 2 and 3 studies can be incorporated into population PK and PK/PD models along with data from well controlled Phase 1 studies to help explain variability among individuals in drug exposure and response. These models are vital tools that can also be used to inform dosing in populations such as pediatrics and those with organ dysfunction.

Our clinical pharmacology and regulatory experts at Rho can help you develop a clinical pharmacology strategy that is right for your development program.  Developing a robust strategy early in your clinical program can help save time and resources. Clinical pharmacology is an important cornerstone of the clinical development of drugs, which this blog post has only begun to introduce. Future blog posts will focus on various aspects of clinical pharmacology, including the types of studies that comprise a clinical pharmacology program, a comparison of clinical pharmacology programs for large and small molecules, evaluations of drug interactions, and regulatory considerations for clinical pharmacology.

References:

FDA Office of Clinical Pharmacology: Good Review Practices: Clinical Pharmacology Review of new Molecular Entity (NME) New Drug Applications and Original Biologics License Applications (BLAs)

Amanda Mathis, Ph.D., Director of Clinical Pharmacology, has over 15 years’ experience working in the pharmaceutical industry.  She received her PhD in Pharmaceutical Sciences from the School of Pharmacy at the University of North Carolina at Chapel Hill in 2007. At Rho, Dr. Mathis provides support regarding clinical pharmacology components of Integrated Product Development programs and Integrated Regulatory Submissions. This includes support for clinical pharmacology strategic planning, gap analyses, support for design, execution, analysis and reporting of clinical pharmacology studies, as well as authoring and reviewing study protocols, reports, and documents for regulatory submissions. She has supported multiple INDs and NDAs, and has authored clinical protocols, study reports, modules for regulatory submissions, briefing packages, and other regulatory documents.