Peptides are gradually reshaping medicine with their superior selectivity and specificity, and at the same time, minimizing the possibility of off-target effects when compared to small molecules. While challenges remain in the development of this therapeutic class, a robust ADME strategy can help overcome these hurdles.
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Nearly 100 peptide drugs have been approved globally, with many more in the preclinical and clinical stages. The approval of semaglutide (Rybelsus®, Novo Nordisk A/S), the first oral GLP-1 receptor agonist for type 2 diabetes and weight control, represents a significant milestone.1
However, drug research and development for this therapeutic class continue to face substantial obstacles, despite recent breakthroughs.
Peptides in particular are susceptible to fast clearance and enzymatic breakdown, and so require non-oral administration via intravenous or subcutaneous methods.
Developing a strong ADME (Absorption, Distribution, Metabolism, and Excretion) approach is critical to overcoming these obstacles.
Designing a robust ADME strategy for peptide therapeutics
Absorption and distribution
Peptides often have low membrane permeability due to their strong polarity and molecular weight. This reduces their capacity to pass lipid membranes, resulting in extremely poor oral bioavailability (often less than 1 %).
They are also particularly sensitive to enzymatic breakdown in plasma, the GI tract, and the liver, resulting in fast elimination from circulation.2
Several approaches can be implemented to solve these concerns while reducing attrition. To begin, passive and active permeability assays (PAMPA, Caco2, and MDCK) should be performed early in the drug development process.
It is also recommended to assess peptide stability in a variety of settings, including blood, plasma, and GI-simulated fluids (FeSSIF/FaSSIF).
The advantage of these assays is that they can be highly personalized by adjusting the medium, pH, and time courses. Physiological conditions can be replicated further, for example, by adding proteases and peptidases that would be found in vivo.
Metabolism and excretion
Peptides are less likely to undergo cytochrome P450-mediated metabolism than small molecules. Peptides are metabolized and removed from the body using two primary mechanisms:
- Rapid proteolytic breakdown in plasma, tissues, and organs, with diverse and unpredictable cleavage mechanisms
- Small (< 5-10 kDa) and hydrophilic peptides are eliminated mostly through renal clearance
Peptides may also interact with renal and hepatic transporters, altering their pharmacokinetic profile.1
To achieve success in later clinical stages, it is crucial to conduct comprehensive in vitro (metabolite detection) and in vivo (pharmacokinetic) research on peptide metabolism.
The complexity of many cleavage routes makes it difficult to fully understand the metabolic destiny of peptides, but with the correct expertise and analytical techniques, it is possible to find metabolic soft spots and guide structural optimization for medicinal chemistry.
To predict renal clearance of peptides, cell-based experiments using cell lines overexpressing renal transporters (e.g., PEPT1, OAT1, OCT2) can be performed to determine whether peptides are substrates or inhibitors of specific transporters, followed by in vivo studies in animal models.
Pharmacokinetics (PK), bioanalysis, and translation
Developing robust bioanalytical methodologies for peptides has multiple significant obstacles. These include the minimal systemic exposure that is typical of peptide therapies, instability in biological matrices, and non-specific binding to laboratory equipment or matrix components.
As a result, method development must prioritize high sensitivity (typically in the near-nanomolar range) and excellent sample stabilization to reduce degradation and proteolysis. This can be accomplished by using protease inhibitors and keeping temperatures moderate during sample handling and extraction.
Plasma protein binding (PPB) is an important pharmacokinetic characteristic that influences the free (active) drug concentration at the target site.
While the Rapid Equilibrium Dialysis (RED) device is often used for small compounds, it is not suggested for use with peptides since it is heavily influenced by adsorption to labware. Instead, ultracentrifugation is favored because it reduces adsorption artifacts and yields more trustworthy PPB data.
Cross-species variations in PPB, peptidase expression, and metabolic cleavage patterns exacerbate in vitro-in vivo extrapolation (IVIVE) and translation to human pharmacokinetics.
These challenges highlight the necessity of DMPK knowledge and advanced PK/PD (pharmacodynamics) modeling, which can have a substantial impact on the success of peptide drug development by directing rational design and increasing predictive accuracy.
Peptide-specific ADME expertise
Understanding the specific obstacles associated with peptide therapy production is critical. With dedicated internal peptide expertise, combined with established protocols and trusted external partners, Concept Life Sciences ensures seamless data integration and rapid turnaround to support your peptide discovery and development.
References
- Xiao, W., et al. (2025). Advance in peptide-based drug development: delivery platforms, therapeutics and vaccines. Signal Transduction and Targeted Therapy, 10(1). DOI: 10.1038/s41392-024-02107-5. https://www.nature.com/articles/s41392-024-02107-5.
- Di, L. (2014). Strategic Approaches to Optimizing Peptide ADME Properties. The AAPS Journal, 17(1), pp.134–143. DOI: 10.1208/s12248-014-9687-3. https://link.springer.com/article/10.1208/s12248-014-9687-3.
Acknowledgments
Produced using materials originally authored by Barbara Marsiglia from Concept Life Sciences.
About Concept Life Sciences
Concept Life Sciences is a leading contract research organisation (CRO) serving the global life sciences industry. For over 25 years, the company, and its heritage companies, have provided consultative and collaborative drug discovery and development services. Our approach, supported by passionate scientists and world-leading capabilities, enables clients to overcome complex scientific challenges across a broad range of therapeutic areas, improving program success rates. The company has successfully helped 29 candidates advance to the clinic.
The company offers sophisticated translational biology services coupled with exceptional end-to-end chemistry capabilities across all modalities, including small molecules, biologics, peptides and cell & gene therapies, with the ability to seamlessly integrate capabilities and provide bespoke solutions to address client needs.
Collectively, the company’s high-quality services and commitment to customer service across the drug development pathway enhance efficiency in drug discovery, helping clients advance their drugs to clinic in as little as 32 months, well ahead of the industry average of 60 months.
Driven by a passion for science, Concept Life Sciences has around 230 employees, with around 70% holding PhDs. The company operates from state-of-the-art UK facilities, headquartered near Manchester, with additional operations in Edinburgh, Dundee, and Sandwich. The headquarters is one of the UK’s largest medicinal chemistry CRO sites with key discovery services all under one roof.
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