Study Guide: What is Pharmacokinetics?
Pharmacokinetics, often defined as what the body does to a substance, refers to the movement of a drug through, through, and out of the body—the time course of its absorption, bioavailability, distribution, metabolism, and excretion.
Pharmacodynamics, defined as what a drug does to the body includes receptor binding, post-receptor effects, and chemical interactions. The effect of medicine influences the onset, length, and severity of the medication. Pharmacokinetics These processes are formulae that sum up the pharmacokinetic activity of most medicines.
- The rate and extent to which drugs are absorbed into the body and distributed to the body tissues
- The rate and pathways by which drugs are eliminated from the body by metabolism and excretion
- The relationship between time and plasma drug concentration.
4 Main phases of Pharmacokinetics
The main processes involved in pharmacokinetics are absorption, distribution, and the two routes of drug elimination, metabolism, and excretion. Together they are sometimes known by the acronym ‘ADME’. Distribution, metabolism, and excretion are sometimes referred to collectively as drug disposition.
Absorption is the process by which drugs enter the body. Given by any route other than intravenously, drug molecules must cross tissue membranes (e.g. skin epithelium, subcutaneous tissue, gut endothelium, capillary wall) to enter the blood.
Distribution is the process by which drugs move around the body. After entering the blood, drug molecules must cross capillary walls to enter the tissues, reach cell membranes and enter cells.
Metabolism is the process by which drugs are chemically altered to make them sufficiently water-soluble for excretion in urine or feces (via the biliary tract). Metabolism occurs in a variety of body organs and tissues, but chiefly in the liver, gut wall, kidney, and skin.
Excretion is the process by which drugs leave the body. Drugs that are sufficiently water-soluble will be excreted unchanged in the urine. Lipid-soluble drugs must be modified to water-soluble metabolites before excretion via the kidney or into the intestine via the bile.
Pharmacokinetics and Pharmacodynamics
Pharmacokinetics versus Pharmacodynamics
Pharmacology is the study of the interactions between drugs and the body. The two broad divisions of pharmacology are pharmacokinetics and pharmacodynamics. Pharmacokinetics (PK) refers to the movement of drugs through the body, whereas pharmacodynamics (PD) refers to the body’s biological response to drugs.
PK describes a drug’s exposure by characterizing absorption, distribution, bioavailability, metabolism, and excretion as a function of time. PD describes drug response in terms of biochemical or molecular interactions.
Understanding the exposure-response relationship (PK/PD) is key to the development and approval of every drug. PK and PD data contribute to much of what is on a drug package insert. Strategic planning of the overall program for a drug and intelligent pharmacokinetic study design can speed the development process.
PK and PD Analyses are 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.
- Predict dosage requirements: PK/PD modeling can help predict dosing requirements early in the development process, making the first dose-range finding studies more informative and consequential.
- Assess changes in dosage requirements: Predicting the biological effect of small dosing changes is important early in the development process, when alterations and formulation changes are common.
- Estimate rate of elimination and rate of 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 the 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.”
We embrace the notion that simplicity and clarity lead to good decisions. We take complex pharmacokinetic principles and make them understandable and usable for common sense drug development. Many of our Pharmacokinetics Consultants have 15-30 years of industry experience. They conduct highly experienced analyses in a fully validated computing environment with the latest PK modeling software.
Pharmacokinetics and Pharmacodynamics Services
PK/PD Analysis and Reporting
- Noncompartmental analyses (GLP and Non-GLP): This type of analysis provides the most elementary 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): Compartmental models are more sophisticated than NCAs, often requiring some biological understanding of a drug’s distribution and action. They can be helpful in answering specific questions such as, “How much of the dose gets into the brain?”, among others. Population PK models are often helpful in explaining the variability in PK data, and can identify demographic variables that might influence dosing recommendations.
Preclinical ADME and Human Studies
- First-Time-in-Human (FTIH): 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 FTIH study enables subsequent human trials.
- Single Ascending Dose (SAD): Usually the first type of trial performed in humans for a new drug, a SAD study investigates the human response to a single dose of a new drug at several dose levels. After the first cohort is successfully administered a new drug, the dose is increased for the next cohort.
- Multiple Ascending Dose (MAD): Often integrated with SAD studies, MAD studies 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 can be the first test of a drug’s efficacy in patients.
- Food Effect: For orally administered drugs, a food effect study is 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): 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 pharmacokinetics and pharmacodynamics of a new drug product are determined.
- Thorough QT (TQT): Empirical evidence has demonstrated that even non-antiarrhythmic drugs can delay cardiac repolarization, an effect that in extreme cases can lead to sudden death. It is unclear why some drugs possess this property and others do not. 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 Impaired: Most drugs are metabolized and partially excreted through the liver. Various medical conditions can affect liver function. Understanding how hepatic impairment affects the pharmacodynamics and pharmacokinetics of a new drug is important for treating patients with impaired liver function.
- Renal Impaired: Most drugs also rely on the kidneys for efficient elimination from the body. Understanding how renal impairment affects the pharmacodynamics and pharmacodynamics of a new drug is important for safe and effective pharmacotherapy in patients with kidney dysfunction.
- Site of Absorption: 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: These studies are used to determine the metabolic and elimination pathways of drugs. They involve administration of an isotopic version of the drug followed by 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 preclinical 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 Services
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.
CDISC Dataset Generation
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.
Study Guide: What is Pharmacokinetics?