Clinical pharmacology is a cornerstone of any clinical development plan, and a well-designed clinical pharmacology program provides valuable information on a new drug’s dosing regimens, effectiveness, and clinically relevant interactions.

In the context of drug development, clinical pharmacology refers to the study of drugs and their interactions in humans, and the relationship between drug exposure and clinical effects. These studies give biomedical companies an understanding of 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.

There are three key questions that biomedical companies should ask at the start of any clinical pharmacology program:
 
1: How are nonclinical and clinical pharmacology teams collaborating to design the study? 
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 when designing clinical pharmacology studies. 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. This data will support decision making as the compound progresses through clinical development.
 
2. What are the short-term objectives of the program? 
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.
 
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. 
 
3. What are the long-term objectives of the program? 
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. 
 
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.

Amanda Mathis, Ph.D., is the Director of Clinical Pharmacology at Rho, a global clinical research organization (CRO). She has supported multiple IND and NDA submissions and has extensive experience authoring clinical protocols, study reports, regulatory submissions modules, briefing packages for regulatory meetings, and other regulatory documents. Dr. Mathis is well versed in a variety of therapeutic areas including rare diseases, infectious diseases (antibacterial, antiparasitic, and antiviral), gastrointestinal disorders, hepatic encephalopathy and liver cirrhosis.