The journey from the lab bench to the bedside is a long, complex, and expensive process. One of the most pressing challenges in pharmaceutical R&D is the high attrition rates of new chemical entities (NCE) in preclinical and clinical drug development, often due to insufficient efficacy, safety issues and economic reasons. Efficacy and safety can be related to absorption, distribution, metabolism, and excretion (ADME) properties, as well as drug metabolism and pharmacokinetics (DMPK), toxicokinetics, and drug interactions.
When a drug fails in Phase I, II or III due to pharmacokinetic liabilities that could have been identified earlier, it represents a significant loss of capital, labor and opportunity. One of the most effective ways to mitigate this risk and shorten the timeline for bringing safe and effective drugs to market is by integrating ADME/DMPK studies early in the drug discovery process.
Strategic early integration of high-throughput in vitro, in vivo and in silico DMPK studies helps researchers to:
- Identify liabilities early, avoiding wasted resources on flawed compounds
- Make smarter go/no-go decisions, accelerating promising candidates
- Reduce late-stage attrition, which is costly and time-consuming
Key Early-Stage DMPK studies
In vitro studies
Conducted using cell-based systems, microsomes, hepatocytes, or recombinant enzymes, these studies are designed to answer critical questions such as:
- Absorption: Can the drug cross biological membranes? Permeability models, such as Caco-2 or PAMPA, simulate intestinal absorption, while solubility testing assesses the feasibility of oral delivery.
- Metabolic stability: Using liver microsomes or hepatocytes, researchers evaluate how quickly a compound is metabolized and identify primary clearance pathways.
- Drug-drug interaction potential: Cytochrome P450 inhibition/induction assays predict whether a compound could interfere with the metabolism of other drugs, a significant safety consideration.
- Plasma protein binding: Determines the fraction of free, pharmacologically active drug in circulation.
- Transporter interactions: Assays targeting influx and efflux transporters such as P-glycoprotein (P-gp) or OATPs reveal how compounds move across membranes, influencing distribution and excretion.
In vivo studies
While in vitro assays provide valuable early insights, in vivo pharmacokinetic studies in preclinical animal models are essential for translating in vitro findings into a whole-body context, refining dose selection and guiding formulation strategies for clinical trials.
- Systemic exposure: Bioavailability, clearance, half-life, and volume of distribution.
- Tissue penetration: The ability of a drug to reach target tissues, including challenging compartments like the brain.
- Dose proportionality and PK/PD relationships: Evaluating how exposure scales with dose and how it correlates with pharmacological effect.
- Toxicity evaluation: Identifying potential liabilities linked to high exposure or accumulation in certain organs.
In silico studies
Advances in computational modeling, machine learning, and AI have made in silico studies an increasingly powerful part of the DMPK toolbox. These approaches leverage existing data to predict ADME and toxicity profiles virtually, reducing the need for extensive wet-lab testing.
- Virtual screening: Compounds with favorable predicted PK properties can be prioritized for experimental evaluation.
- Predictive modelling: Physiologically-based pharmacokinetic (PBPK) models combine in vitro and in vivo data to predict human pharmacokinetics and dosing strategies.
- Risk filtering: In silico tools help eliminate high-risk candidates before costly experimental studies are initiated.
When applied strategically, in silico approaches complement experimental DMPK work, enabling faster, more cost-effective candidate selection and optimization.
Strategic Integration: From Discovery to Clinical Development
For DMPK insights to truly influence the success of drug development, they must be strategically integrated from the earliest stages. Too often, DMPK scientists are brought in only after lead compounds have been selected, limiting their ability to shape development in meaningful ways. Instead, DMPK should be embedded throughout the discovery and development lifecycle.
Early engagement allows DMPK experts to contribute to lead optimization, helping prioritize and refine compounds based on metabolic stability, permeability, and potential liabilities. With timely feedback loops between DMPK scientists and medicinal chemists, teams can avoid unnecessary iterations and accelerate the identification of viable clinical candidates.
This collaborative model also supports translational DMPK, the bridge between preclinical and clinical development. By applying physiologically-based pharmacokinetic (PBPK) modeling and in vitro-in vivo extrapolation (IVIVE), researchers can use early DMPK data to predict human pharmacokinetics, optimize first-in-human (FIH) dosing strategies, and foresee potential challenges such as accumulation, metabolite exposure, or drug-drug interactions.
A well-integrated DMPK strategy enables data-driven decision-making at every stage, resulting in more targeted and efficient clinical trials.
This includes:
- Setting appropriate dose ranges for clinical trials
- Identifying vulnerable patient populations
- Anticipating variability in drug exposure due to genetic polymorphisms or comorbidities
- Avoiding development delays related to regulatory concerns about drug metabolism
Ultimately, this approach facilitates faster, safer, and more efficient progression from discovery through clinical development, thereby increasing the likelihood of success and regulatory approval.
Conclusion
In an era where efficiency and precision are essential, early integration of DMPK studies is no longer optional; it’s essential. Understanding a drug’s ADME characteristics from the outset allows development teams to make informed, strategic decisions that can prevent costly setbacks, optimize resource allocation, and accelerate the path to market.
Companies that prioritize early DMPK often experience shorter timelines, improved success rates in clinical trials, and stronger licensing or partnership opportunities due to well-characterized assets.
Crown Bioscience offers comprehensive in vitro and in vivo solutions that deliver accurate and reliable data to help you make informed decisions and achieve regulatory success early, enabling you to transition from preclinical studies to clinical trials with confidence. Learn more
Advance your drug program with precision DMPK analysis
