What is DMPK, and why does it matter in drug development?

Drug metabolism and pharmacokinetics (DMPK) are crucial components in drug development. Imagine predicting how a drug will behave in the human body before it even reaches clinical trials. That’s the power of DMPK studies. By understanding the metabolism and pharmacokinetics of a drug, researchers can foresee potential risks and optimize drug design for better therapeutic outcomes.

What is DMPK?

DMPK is a core discipline in drug development that considers the biotransformation of a drug compound and other pharmacokinetic properties to assess drug safety. DMPK studies allow drug developers to experimentally evaluate the intrinsic properties of a drug candidate to validate that it can and will be cleared from the body, when administered to a patient, without producing harmful byproducts (metabolites), reaching dangerous exposure levels (toxicity), or causing adverse side effects. This class of in vitro and in vivo studies can also help drug developers to predict potential risks, early in drug development, as well as provide nonclinical evidence to justify decisions or explain clinical observations.

A vital risk DMPK studies can help evaluate is the potential for drug-drug interactions (DDIs), occurring when adverse effects result from a patient taking multiple medications. Investigating a drug’s interactions with metabolizing enzymes and drug transporters in vitro can identify risks before first in-human trials and help the drug developer anticipate and plan clinical DDI studies or labeling restrictions if necessary.

Why DMPK matters

1. Ensures drug safety: DMPK studies help identify harmful byproducts (metabolites) or toxicity risks, ensuring drugs are safe for human use.
2. Predicts drug behavior: By studying how a drug is absorbed, distributed, metabolized and excreted, researchers can predict its pharmacological effects and efficacy.
3. Minimizes risks: DMPK can uncover potential DDIs, which is crucial for patients taking multiple medications.
4. Optimizes drug design: Insights from DMPK studies enable developers to refine drug properties to achieve better therapeutic outcomes, such as increased bioavailability or longer half-life.
5. Justifies clinical decisions: It provides nonclinical evidence that supports regulatory approval and clinical trial design.

In vitro DMPK studies

In vitro DMPK studies are essential in drug development to evaluate how a drug interacts with biological systems. These studies use methods like liver microsomes, hepatocytes or plasma to predict a drug’s behavior in humans before advancing to clinical trials.

In vitro studies, such as liver microsomes or cryopreserved hepatocytes, contain relatively high concentrations of drug-metabolizing enzymes (DMEs). These systems allow drug developers to explore their drug candidate’s metabolism by collecting experimental data to answer specific, relevant questions about how a drug will interact with human or other species’ cells at primary sites of metabolism.

There are three major in vitro drug metabolism studies:

• Metabolic stability: Determines a drug’s ability to be converted to metabolites by measuring the rate of intrinsic clearance by drug-metabolizing enzymes.
• Metabolite characterization: Identifies which metabolites may be formed from the parent drug and if any are unique to humans or disproportionately higher in humans than preclinical models.
• Reaction phenotyping: Provides insight into which cytochrome P450 (CYP) enzymes are responsible for the metabolism of a drug candidate and identifies its potential for metabolism-mediated DDIs.

Within each of the drug metabolism studies described above, sponsors often elect to use test systems from multiple species in addition to humans. Comparing potential toxicology with each other and to human results allows them to choose a species for in vivo and in vitro definitive studies that has a similar metabolic profile to humans (including metabolites formed and metabolic pathway) and allows them to identify any human-specific metabolites.

Metabolism-mediated drug interactions investigate drug-metabolizing enzymes as part of the determination of a compound’s potential for drug-drug interactions, including:

• Enzyme inhibition
• Enzyme induction

These studies are specified in the FDA’s guidance for industry documents as tools to predict a drug’s perpetrator potential in metabolism-mediated drug interactions. They are designed to use test systems with average enzyme expression (e.g., a pool of liver microsomes from 200 human donors, or several lots of human hepatocytes) to determine if a compound is likely to induce (upregulate) or inhibit drug-metabolizing enzymes that are responsible for the metabolism of other (victim) drugs which may also be prescribed to a patient.

In vivo DMPK studies

In vivo ADME (Absorption, Distribution, Metabolism and Excretion) studies using radiolabeled drugs are typically conducted pre-IND through Phase I of clinical trials. In vivo models reflect the combined effects of permeability, distribution, metabolism and elimination before administration to a human.

Key points of in vivo studies:

• Measure parent drug and metabolite exposure levels.
• Determine potential toxicities and identify areas of concern such as low absorption or high clearance.
• Validate the choice of preclinical species, define the route of elimination, and quantify the contribution of metabolism.

Comparing in vitro and in vivo methods

In vitro and in vivo studies differ significantly in their approach, environment and purpose when investigating DMPK. Here is how:

Experimental setting

• In vitro: conducted in controlled lab environments using isolated systems like cell cultures, liver microsomes or enzymes. They are simplified models focusing on specific aspects of drug metabolism.
• In vivo: conducted within living organisms, typically using animal models or human subjects

Predictive scope

• In vitro: allows for preliminary understanding of specific ADME properties, e.g., enzyme interactions or permeability, and helps identify potential challenges like toxicity or low bioavailability.
• In vivo: Provides comprehensive data on the drug’s impact and pharmacological effects, including systemic absorption, tissue distribution, metabolic pathways and elimination.

Time and cost

• In vitro: faster and cost-effective, often used as a screening tool early in development.
• In vivo: more time-intensive and expensive, usually performed later to confirm findings and predict human responses.

Biological complexity

• In vitro: reduces complexity, allowing focused studies but may lack the dynamic interplay of living systems.
• In vivo: captures complex interactions, like immune responses, but can be more unpredictable.

Both methods complement each other, with in vitro studies an essential precursor to in vivo testing. Together, they form a robust framework for understanding drug behavior before clinical trials.

DMPK studies are indispensable in drug development, providing critical insights into drug safety and efficacy. By leveraging advanced DMPK software solutions, you can streamline your workflows and make informed decisions with confidence.

Transform your DMPK workflows with IDBS’ innovative solutions

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About the author

Lisa Postava, Product Marketing Manager, Preclinical & Clinical, IDBS

Lisa Postava is the Product Marketing Manager for Preclinical and Clinical at IDBS. Prior to IDBS, she worked in both research and clinical settings both at the University of Pittsburgh and in various marketing and product management roles for 20 years at Thermo Fisher Scientific with her last role being Director of Strategic Marketing, NA.

 

 

References: 

1. In Vitro ADME Assays and Services | Charles River
2. The A-Z Guide of DMPK Assays and How to Find the Right OneWhat is DMPK and how does it fit into drug development?