The High Cost of Failure: Why Early Assessment is Paramount
Drug development is a complex, lengthy, expensive and uncertain journey, often spanning over a decade, on average, and costing billions of dollars. Despite advances in science and technology, the attrition rate in late-stage drug development remains high at over 80%, particularly in Phase II and III clinical trials. Many of these late-stage failures are linked to unforeseen issues with pharmacokinetics and metabolism profiles, such as poor bioavailability, rapid clearance, or drug-drug interactions.
Preclinical research is fundamental to the success of drug development, and drug metabolism and pharmacokinetics (DMPK) are foundational pillars in this process. Early-phase in vitro DMPK studies have the potential to significantly reduce the risks of late-stage failures by helping anticipate a compound’s absorption, distribution, metabolism and excretion (ADME) properties. Proactively identifying potential drug-drug interactions, low bioavailability or high metabolic instability, among others, can help inform decisions regarding terminating or strategically modifying compounds with unfavorable ADME properties, thus adhering to the principle of ‘fail early, fail cheap’.
Early in vitro DMPK studies not only enable smarter resource allocation and help prioritize the most viable candidates but also reduce financial risk by avoiding late-stage failures, allowing researchers to transition from preclinical studies to clinical trials with confidence. Thus, improving early access to potentially life-saving therapies for patients.
Unveiling Drug Behavior: Key In Vitro DMPK Assays
In vitro DMPK studies employ a range of biochemical and cell-based assays to simulate how a drug might behave in the body. These predictive models are indispensable in early drug discovery and for guiding lead optimization and candidate selection with favorable pharmacokinetic profiles. Key assays include:
1. Metabolic Stability Assays
“How quickly will my parent compound be metabolised?”
Using liver microsomes or hepatocytes from humans or animals, these assays evaluate the rate at which a compound is metabolised, influencing its half-life and clearance. A drug that is rapidly broken down may have a short duration of action, requiring frequent or higher dosing to maintain therapeutic levels in the body. Conversely, a compound with good metabolic stability is more likely to have a longer half-life and sustained efficacy.
2. Permeability Assays (Caco-2, PAMPA)
“How well does my drug cross cell membranes?”
These assays assess a drug’s ability to cross biological membranes, particularly the intestinal epithelium, which is crucial for oral absorption and bioavailability. The colon carcinoma (Caco-2) cell permeability model mimics human intestinal barriers, whereas the Parallel Artificial Membrane Permeability Assay (PAMPA) is a non-cell-based method for evaluating passive, transcellular intestinal absorption. Poor permeability flags challenges in a drug entering circulation and achieving effective systemic exposure.
3. Plasma Protein Binding
“How much of the drug is bound to plasma proteins, and what concentration of free drug is available to reach the target?”
Plasma protein binding assays measure the degree to which a compound binds to proteins within plasma. Only the unbound (free) fraction of a drug is pharmacologically active and available for distribution. The less bound a drug is, the more efficiently it can traverse cell membranes and be available for distribution to other organs and tissues. In contrast, drugs that are highly bound to plasma proteins are confined to the vascular space, having a low volume of distribution and reducing the amount of drug available to reach the target tissue, thereby reducing efficacy.
4. CYP450 Inhibition and Induction Assays
“Does my compound interfere with the metabolism of co-administered drugs?”
These assays identify potential drug-drug interactions or flag compounds that exhibit non-linear PK behavior.
The Cytochrome P450 (CYP450) family of enzymes is responsible for metabolizing most drugs seen in clinical practice. Inhibition of CYP450 enzymes may result in higher-than-intended levels of the affected drug in the body, potentially leading to adverse effects or toxicity. Whereas the induction of these enzymes by a compound increases the metabolism and clearance of a co-administered drug, thereby reducing plasma levels and potentially leading to changes in drug concentration and treatment failure.
5. Transporter Assays
“How is my drug absorbed, distributed and excreted?”
Transporter assays evaluate how drugs interact with influx (uptake) transporters, such as P-glycoprotein (P-gp), and efflux (outward movement) transporters, including the organic anion-transporting polypeptides (OATPs). They assess drug absorption, distribution into tissues (such as the brain), and excretion. Thus, predicting drug-drug interactions, potential toxicity, and tissue-specific accumulation.
Together, the data generated from these in vitro DMPK studies guide informed decisions regarding the optimization of chemical structures, enhancing metabolic stability, reducing transporter liability, and fine-tuning permeability, resulting in drug candidates with improved pharmacokinetic properties and a higher probability of success.
From Bench to Bedside: Translating In Vitro Data to Clinical Success
The strength of in vitro DMPK studies lies in their predictive power, enabling a strategic transition from early discovery to in vivo and clinical phases of drug development.
By understanding a compound’s in vitro ADME profile and employing computational modelling and simulation, researchers can predict likely human pharmacokinetics, estimate human doses and oral dosing feasibility, and anticipate potential safety concerns, such as drug accumulation or drug-drug interactions.
This foundational in vitro data can support and enhance the translatability to in vivo efficacy of an optimised lead, informing the careful design of more targeted and efficient preclinical in vivo studies. The ultimate goals of this translation process are to predict a safe and effective human therapeutic dose, identify patient populations at higher risk of adverse effects due to metabolic variations, and increase clinical success through the design of smarter clinical trials.
A robust in vitro DMPK strategy executed early in development provides strong scientific data to support the progression, significantly de-risking the journey towards clinical approval.
Conclusion
An early-stage in vitro DMPK strategy is crucial in successful drug development, optimising strategic leads, mitigating risks, and accelerating progression from discovery through to clinical trials and approval. By identifying liabilities in ADME properties upfront, researchers can make informed decisions, eliminate weak candidates early, reduce late-stage failures and focus resources on compounds with genuine clinical promise.
Crown Bioscience provides industry-leading Drug Metabolism and Pharmacokinetics (DMPK) and Absorption, Distribution, Metabolism, and Excretion (ADME) services designed to streamline your drug discovery and drug development process.
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