Clinical pharmacology is the study of the interactions between drugs and the human body. Pharmacokinetics and pharmacodynamics are two broad divisions within clinical pharmacology. The complex, biochemical interactions that occur between the body’s natural processes and the chemical composition of a pharmaceutical drug are measured and described by pharmacokinetics and pharmacodynamics which both play a pivotal role in determining a drug’s safety and efficacy.
Regulatory agencies, such as the FDA, are responsible for approving new drugs or deciding whether or not a drug should be taken off the market. Regulatory agencies are also responsible for ensuring that all available drugs are effective and safe for human use. Understanding the safety and effectiveness of any drug depends, in part, on pharmacokinetics and pharmacodynamics.
Pharmacokinetics vs. Pharmacodynamics
The main difference between pharmacokinetics and pharmacodynamics is that pharmacokinetics (PK) is defined as the movement of drugs through the body, whereas pharmacodynamics (PD) is defined as the body’s biological response to drugs. In other words, PK describes a drug’s absorption, distribution, metabolism, and excretion (also known as ADME) and PD describes how biological processes in the body respond to or are impacted by a drug. Put in the simplest terms, pharmacokinetics is what the body does to the drug and pharmacodynamics is what the drug does to the body.
While PK describes a drug’s exposure by characterizing its ADME properties and bioavailability as a function of time, PD describes a drug’s response in terms of biochemical or molecular interactions. PK/PD together can be thought of as an exposure/response relationship.
Understanding the exposure-response relationship (PK/PD) is key to the development and approval of every drug. PK and PD data contribute to about 25% of what is in a drug package insert or drug label. Strategic planning of the overall drug development program and an intelligent pharmacokinetic study design can accelerate the development process to help ensure safety and efficacy endpoints are achievable.
The Importance of Pharmacokinetic and Pharmacodynamic Analyses
PK and PD analyses are important because they help us understand how drugs behave in the body and how the body reacts to drugs, respectively. Drug developers use insights gained from PK and PD analyses to design better clinical studies (i.e., what dose to use or how different drugs interact with each other in the body). Clinicians use the information from PK and PD analyses (as presented in the drug label or package insert) to treat different types of patients (e.g., patients with and without renal impairment or elderly versus younger patients).
How to Use Pharmacokinetic and Pharmacodynamic Analyses
PK and PD analyses can be used to determine a number of important drug development parameters related to clinical study design. PK and PD analyses can be used to:
- Characterize drug exposure: With the exception of drugs delivered intravenously, only a fraction of a drug’s dose is absorbed and pharmacologically active. Quantifying the rate and magnitude of exposure to a drug is critical for determining how best to guide its use in the clinic.
- Determine an appropriate dose for a clinical study: PK and PK/PD modeling can help predict dosing requirements early in the development process (i.e., dose justification), making the first dose-range finding studies informative and consequential.
- Assess changes in dose requirements: Assessing and predicting the effect of dosing changes is important early in the development process to provide insights into designing better clinical studies.
- Estimate the rate of elimination and absorption: Knowing how quickly a drug is absorbed and eliminated can help make decisions regarding formulation design and dosing regimens.
- Assess relative bioavailability/bioequivalence: Comparing the extent of a new formulation’s absorption to an existing formulation can often help demonstrate therapeutic advantages.
- Characterize intra- and inter-subject variability: High variability can quickly derail clinical development programs. Understanding how a drug’s PK and PD change within and between individuals can help design clinical trials in ways that reduce variability and make the results more robust.
- Understand concentration-effect relationships: The concentration-effect relationship is the cornerstone of pharmacodynamics. Identifying the variables that affect this relationship is critical for a successful development program.
- Establish safety margins and efficacy characteristics: Successful drugs have clearly defined therapeutic windows. PK/PD modeling can help determine dosing thresholds. Sola dosis facit venenum… “The dose makes the poison.”
Pharmacokinetics and Pharmacodynamics Services
Our PK and PD services include:
- PK/PD analysis and reporting
- Designing and interpreting pre-clinical ADME and clinical studies
- Dosing simulations
- Risk analysis
- Creating integrated PK study reports or standalone PK reports
- Data management and CDISC dataset generation
PK/PD Analysis and Reporting
- Noncompartmental Analyses: This type of analysis provides the most common PK information for a drug (i.e., the rate and extent of absorption and elimination). NCAs are essential for characterizing new drug products and can help guide development at each stage.
- PK/PD Modeling and Simulation: Compartmental and population PK models are more sophisticated than NCAs, often requiring some biological understanding of a drug’s distribution and mechanism of action. These techniques can be helpful in answering specific questions such as, “How much of the dose gets into the brain?” Population PK (popPK) models are often helpful in explaining the variability in PK data and can identify demographic variables that might influence dosing recommendations.
Designing and Interpreting Pre-clinical ADME and Clinical Studies
- First-in-Human (FIH) Study: The first PK clinical trial of a new drug in human subjects is a critical juncture in its development. Estimating the appropriate dose and designing the study to capture all relevant metrics are essential to ensuring an FIH study leads to subsequent human trials.
- Single Ascending Dose (SAD) Study: SAD studies are usually the first type of trial performed in humans for a new drug. SAD studies investigate the human response to a single dose of a new drug at several dose levels. After the first cohort is successfully dosed with the drug, the next cohort of subjects receives a higher dose of the drug.
- Multiple Ascending Dose (MAD) Study: MAD studies are often integrated with SAD studies and investigate the human response to multiple doses of a new drug at several dose levels. Since most drugs are designed for repetitive administration, MAD studies are important to understand how the drug will behave at steady state.
- Food Effect Study: Food effect studies are for orally administered drugs and are important for understanding the effect that food can have on the absorption of a new drug product. The results of a food effect study are often critical for informing dosing recommendations.
- Drug-Drug Interaction (DDI) Study: Polypharmacy, or the concomitant administration of multiple drugs, is a widespread phenomenon in modern medicine. As a result, it is essential that the impact of various drugs on the PK and PD of a new drug product are determined.
- Thorough QT (TQT) Study: Empirical evidence has demonstrated that even non-antiarrhythmic drugs can delay cardiac repolarization, an effect that in extreme cases can lead to sudden death. Thus, a TQT study is necessary for measuring the effect of a new drug on the QT interval (an ECG metric that serves as a surrogate for detecting cardiac repolarization).
- Hepatic Impairment Study: Most drugs are metabolized and partially excreted through the liver. Various medical conditions can affect liver function. Understanding how hepatic impairment affects the PK and PD of a new drug is important for treating patients with impaired liver function.
- Renal Impairment Study: Most drugs rely on the kidneys for efficient elimination from the body. Understanding how renal impairment affects the PK and PD of a new drug is important for safe and effective pharmacotherapy in patients with kidney dysfunction.
- Site of Absorption Study: Different parts of the gastrointestinal tract have different properties, and depending on the physicochemical attributes of a drug, one part of the GI tract may be a more attractive site for absorption than another. Determining the site of absorption can help make decisions regarding a drug’s formulation.
- Radio-Labeled Mass Balance (ADME) Study: Mass balance studies are used to determine the metabolic and elimination pathways of drugs. They involve administering an isotopic version of the drug followed by the collection of biological fluids.
Once a model has been constructed, different dosing regimens can be simulated to predict exposure. This type of service can save valuable time and resources when trying to design and justify dosing regimens in clinical studies
By integrating PK/PD models with pre-clinical data, probabilistic risk analysis can make drug development more efficient by eliminating candidates with a high risk of failure in clinical trials.
Integrated PK Study Reports or Standalone PK Reports
Ensuring that a study report conveys the appropriate information to health authorities requires subtle messaging and a rigorous attention to detail.
Data Management and CDISC Dataset Generation
In addition to storage and security, considerations regarding data collection and interrogation should be made at the beginning of a study to maximize the utility of a dataset after it is locked. Read more about our data management services here.
All clinical data submitted to health authorities must conform to the Clinical Data Interchange Standards Consortium (CDISC) format. Our data managers specialize in this type of reporting and are extremely efficient at CDISC conversion.
Contact our PK/PD Experts for Guidance
Nuventra is a leading PK/PD science consulting group in terms of our expertise and customer service. We provide exceptional clinical & nonclinical noncompartmental PK analyses to support drug development programs. Our flexible reporting options range from simple outputs to robust submission-ready pharmacokinetic reports.
Contact us today to learn more about how our variety of PK analyses services can benefit your program. We enjoy working closely with our clients to determine the most appropriate and cost-effective options for each unique drug development program.