ADME/DMPK Studies

Select lead compounds with appropriate permeability and absorption characteristics for optimal target delivery. Identify metabolism-, excretion- and drug interaction-related risks early to de-risk your pipeline.

• High-throughput ADME (HT-ADME)
• Pharmacokinetic screening
• Discovery bioanalysis

ADME/DMPK assessment needs during drug development evolve uniquely for every compound. Investigate drug interactions with various tissues, organs, and barriers, and learn how these may impact your project.

• Metabolite profiling
• SOLVO drug transporter assays
• Pharmacokinetics / Toxicokinetics
• Tissue distribution / QWBA

Certain ADME datasets, especially drug-drug interaction (DDI) investigations, need to be provided for regulatory submissions at different stages, including IND filing. Start building your data package.

• In vitro ADME
• In vivo ADME
• IND-enabling studies

Movement of a drug from its site of administration into the bloodstream is defined as absorption. While most drugs are absorbed by passive permeation, some need carrier-mediated transport. Every drug is different, and many characteristics play a role in the absorption of a drug, like physicochemistry characteristics (e.g., molecular weight, hydrophobicity, solubility), physiological characteristics (e.g., blood flow, intestinal motility, membrane permeability) and biochemical characteristics (e.g., efflux, metabolism) characteristics and the formulation itself.

ADME/DMPK studies to consider: aqueous solubility, in vitro permeability, in vitro drug transporters, in vitro dermal absorption and in vivo pharmacokinetics, and in vivo dermal absorption.

Once the drug has been absorbed into the bloodstream it is transported or differentially distributed from the blood to the site of action within the body. Not all compounds distribute equally throughout the body. This is determined by the compounds physicochemistry and ability to permeate into tissues and cells and by the blood flow to tissues but also by binding of the compound to proteins and by specific transporter processes.

ADME/DMPK studies to consider: in vitro plasma protein binding, in vitro RBC partitioning, melanin binding, in-vitro uptake/efflux transporters, barrier tissue models, in vivo tissue distribution, quantitative whole body autoradiography (QWBA), cerebrospinal fluid collection, in vivo pharmacokinetics.

In order to facilitate the excretion of a drug from the body, the drug is chemically altered by enzymes to increase its polarity and water solubility. This process is called metabolism. Most metabolism takes place in the liver. The family of enzymes that is mainly involved in the first steps of the metabolic process are the cytochrome P450 enzymes (CYP450). Another important enzyme family that is responsible for a conjugation reaction (glucuronidation) is the UGT family.

ADME/DMPK studies to consider: metabolic stability, metabolite profiling/comparative species metabolism, CYP/ UGT characterization, CYP/UGT inhibition, CYP induction, drug-drug interaction studies (DDI), reactive metabolite assessment, covalent binding.

Drug (unchanged) and/or its metabolites can leave the body via different routes of excretion, e.g. urine, bile, feces, expired air, and sweat. This can either be a passive process (e.g. glomerular filtration in the kidneys) or an active secretion process mediated by transporters.

ADME/DMPK studies to consider: in vitro transporters, mass balance studies (excreta and expired air collection via metabolism cages), bile cannulation models.

ADME is defined as Absorption, Distribution, Metabolism and Excretion and is a core discipline within drug, chemical and agrochemical discovery, development and post-marketing product development process that describes the

• (A) Absorption, the movement of a compound from the site of administration into the blood
• (D) Distribution, the movement of compounds throughout the body
• (M) Metabolism, the transformation of a compound to its metabolites within the body
• (E) Excretion, the elimination of a compound and its metabolite from the body

ADME studies are critical parts of any drug discovery and development program and inadequate ADME properties can cause irreversible disruption to the entire process.

There are numerous guidance documents that recommend when and how to evaluate the ADME properties. Each describes the agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. Charles River scientists, scientific advisors and regulatory personnel are available to assist in the interpretation and recommendations for any ADME/DMPK program.

ICH S3A Toxicokinetics: The assessment of Systemic Exposure in Toxicity studies (FDA Mar 1995)
ICH S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies (FDA Mar 1995)
ICH Topic M3 (R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (FDA Jan 2010)
FDA Guidance for Industry: Safety Testing of Drug Metabolites (Feb 2008)
FDA Draft guidance for Industry: In vitro Metabolism and Transporter-Mediated Drug-Drug Interaction studies (Oct 2017)
EMA: Guideline on the Investigation of Drug Interactions (Jan 2013)

ADME studies are important for several reasons, including:

• Predicting how a drug will behave in the body, including how much is absorbed, where it is distributed, how it is metabolized, and how it is excreted.
• Identifying potential drug interactions.
• Assessing the safety and efficacy of a drug candidate.
• Optimizing the formulation and dosage of a drug.
• Complying with regulatory requirements.

ADME studies are conducted at all stages of drug discovery and development, from early preclinical testing to late-stage clinical trials. The data collected from these studies is used to make informed decisions about whether to advance a drug candidate to the next stage of development, or to terminate development altogether.

Here are some specific examples of how ADME studies are used in drug development:

• Drug absorption: ADME studies can be used to determine how much of a drug is absorbed into the bloodstream when it is administered orally, topically, or by injection. This information is important for determining the optimal dosage regimen and for avoiding potential toxicity.
• Drug distribution: ADME studies can be used to track how a drug is distributed throughout the body after it is absorbed. This information is important for understanding how the drug will reach its target site and for identifying potential side effects.
• Drug metabolism: ADME studies can be used to identify the enzymes that metabolize a drug and the metabolites that are formed. This information is important for understanding the drug's half-life, its potential for drug interactions, and its overall safety and efficacy.
• Drug excretion: ADME studies can be used to determine how a drug is excreted from the body, whether in urine or feces. This information is important for understanding the drug's half-life and for identifying potential toxicity.

Overall, ADME studies are essential for the development of safe and effective drugs. By understanding how a drug is absorbed, distributed, metabolized, and excreted, researchers can better predict its behavior in the body and optimize its formulation and dosage.

ADME tests can be performed in vitro (outside of a living organism) or in vivo (in a living organism).

In vitro ADME tests are typically used in early drug discovery to rapidly screen a large number of compounds for their ADME properties. These tests are often performed on cell cultures or microsomal fractions of liver or other tissues.

In vivo ADME tests are typically performed later in drug development, after a compound has been shown to have promising ADME properties in vitro. In vivo ADME tests are more expensive and time-consuming than in vitro tests, but they provide more accurate data about how a drug will behave in a living organism.

ADME and DMPK are closely related, but they are not exactly the same.

ADME stands for absorption, distribution, metabolism, and excretion. It is a broader term that refers to all of the processes that a drug goes through in the body.

DMPK stands for drug metabolism and pharmacokinetics. It is a narrower term that focuses on the specific processes of drug metabolism and drug movement in the body.

DMPK is a subset of ADME. It is specifically concerned with how a drug is metabolized by the body and how it is distributed to different tissues. ADME studies, on the other hand, can also include studies on how a drug is absorbed into the body and how it is excreted. In general, DMPK studies are more focused on the mechanistic aspects of drug metabolism and distribution, while ADME studies are more focused on the overall behavior of a drug in the body.

Both ADME studies and DMPK studies are essential for the development of safe and effective drugs. By understanding how drugs are absorbed, distributed, metabolized, and excreted, researchers can better predict their behavior in the body and optimize their formulation and dosage.

Drug metabolism and pharmacokinetics (DMPK) studies are a type of preclinical study that is used to assess the absorption, distribution, metabolism, and excretion (ADME) of a drug candidate. This information is essential for understanding how a drug will behave in the body and for designing safe and effective clinical trials.

DMPK studies can be performed in vitro or in vivo. In vitro DMPK studies are typically used to screen a large number of compounds for their ADME properties and to identify promising candidates for further development. In vivo DMPK studies are typically performed later in drug development, after a compound has been shown to have promising ADME properties in vitro.