Overview

Pharmacodynamic (PD) biomarkers indicate how a drug affects its target, like a receptor triggering a signalling cascade. They reflect the drug’s impact on the body’s biological or physiological functions. Unlike pharmacokinetics, which focuses on how the body processes a drug, pharmacodynamics explores its effects and mechanisms. These markers are vital in clinical trials, helping assess a drug’s efficacy, safety, and optimal dosage, and in individualizing treatments. They’re crucial in drug development, aiding researchers and healthcare pros in understanding a drug’s interactions and suitability for its intended use. Developing New Chemical Entities (NCE) involves discovering, designing, and synthesizing novel compounds for therapy. Bioanalysis, quantitatively measuring drugs and their metabolites in biological samples, is key in NCE development.

Challenges & Considerations

Strategies for PD Biomarker Quantitation

Quantifying Pharmacodynamic (PD) biomarkers in bioanalysis involves careful planning and execution to ensure accurate and reliable measurement of the biological responses to a drug. Here are the strategies concerning requirements and rationale for PD biomarker quantitation in bioanalysis.

Veeda’s Capabilities & Approach for Novel Drug Development Program

Bioanalysis is a vital part of drug development, focusing on accurately measuring drugs and their by-products in biological samples. A successful bioanalysis strategy involves method development, validation, and application in clinical studies.

• At Veeda, method development involves extensive research, considering various factors like drug properties, dose, linearity range, extraction protocols, chromatography, and equipment. Method validation includes experiments ensuring compliance with regulations, such as selectivity, accuracy, precision, sensitivity, matrix effects, and stability studies. In clinical sample analysis, it’s crucial for determining drug levels in biological samples. Incurred sample reanalysis validates reported sample analyte concentrations, ensuring reliability
• Employing emerging technologies like LC-MS/MS machines, ICP-OES, LIMS, and BSL-2 labs enhances our capabilities. Quality management systems (QMS) established protocols ensuring consistent quality standards, customer satisfaction, and regulatory compliance
• Data analysis and statistical approaches at Veeda derive meaningful insights from experimental results, ensuring their reliability and validity
• Regulatory compliance involves adherence to industry-specific laws, guidelines, and standards
• Cross-validation with clinical endpoints ensures alignment between laboratory analyses and clinical outcomes, establishing correlations between measured biomarkers/drug concentrations and therapeutic effects/safety outcomes

Our Expertise in PD Biomarker Method Development & Validation

Conclusion

Bioanalysis is pivotal in identifying, measuring, and characterizing Pharmacodynamic (PD) markers, which indicate a drug’s biological effects in an organism. Its role involves:

• Identification: Using techniques like mass spectrometry, immunoassays, and chromatography to screen and identify potential PD markers
• Quantification: Developing precise methods to measure PD markers accurately
• PK/PD Modelling: Integrating bioanalytical data into models for predictive insights on drug concentration and PD marker levels
• Dose-Response Assessment: Analyzing concentration-response relationships to establish dose-response curves
• Early Phase Development: Using bioanalytical data to guide decisions about dosing, further development, and safety concerns
• Safety Assessment: Identifying and measuring biomarkers that signal potential safety issues during drug development

Reference:

1. Abbas M, Alossaimi MA, Altamimi AS, Alajaji M, Watson DG, Shah SI, Shah Y, Anwar MS. Determination of α1-acid glycoprotein (AGP) concentration by HPLC in patients following local infiltration analgesia for primary total hip arthroplasty and its relation to ropivacaine (total and unbound). Frontiers in Pharmacology. 2023;14
2. Kandoussi H, Zeng J, Shah K, Paterson P, Santockyte R, Kadiyala P, Shen H, Shipkova P, Langish R, Burrrell R, Easter J. UHPLC–MS/MS bioanalysis of human plasma coproporphyrins as potential biomarkers for organic anion-transporting polypeptide-mediated drug interactions. Bioanalysis. 2018 May;10(9):633-44
3. Shin S, Fung SM, Mohan S, Fung HL. Simultaneous bioanalysis of l-arginine, l-citrulline, and dimethylarginines by LC–MS/MS. Journal of Chromatography B. 2011 Mar 1;879(7-8):467-74
4. Yin F, Ling Y, Martin J, Narayanaswamy R, McIntosh L, Li F, Liu G. Quantitation of uridine and L-dihydroorotic acid in human plasma by LC–MS/MS using a surrogate matrix approach. Journal of Pharmaceutical and Biomedical Analysis. 2021 Jan 5;192:113669
5. US Food and Drug Administration; U.S. Department of Health and HumanServices; Food and Drug Administration; Center for Drug Evaluation and Research (CDER); Center for Veterinary Medicine (CVM). Bioanalytical Method Validation: Guidance for Industry; U.S. Department of Health and Human Services, Food and Drug Administration: Silver Spring, MD, 2018

Introduction

Chronic Obstructive Pulmonary Disease (COPD) and Asthma are significant respiratory conditions that affect millions worldwide. In 2019, COPD accounted for 3.3 million deaths and 74.4 million disability-adjusted life years (DALYs), with a global prevalence of 212.3 million cases. Meanwhile, the prevalence of Asthma has been rising due to increased life expectancy and changing demographics. Additionally, the overlap of Asthma and COPD cases has become more frequent, presenting unique challenges in diagnosis and treatment.

Current Treatment Landscape

1. Bronchodilators: The use of both short-acting inhaled bronchodilators (albuterol and ipratropium) as rescue therapy and long-acting bronchodilators (LABAs and LAMAs) has become common. Several new bronchodilators are in development, showing promise for future therapies.
2. Muscarinic Antagonist–β2-Agonists (MABAs): MABAs are under clinical trials, though challenges exist in balancing their LABA and LAMA activity.
3. New Corticosteroids: Fluticasone furoate, a once-daily inhaled corticosteroid (ICS) in combination with vilanterol, offers a new option. However, safety concerns related to corticosteroids remain.
4. Phosphodiesterase Inhibitors: Roflumilast is currently marketed as an anti- inflammatory treatment in COPD, but its narrow therapeutic window limits its use.
5. Kinase Inhibitors: Some kinase inhibitors have shown promise in COPD and Asthma models, but challenges in specificity and side effects require further research.
6. Mediator Antagonists: CRTh2 antagonists, cytokine inhibitors, and protease inhibitors have been widely used in Asthma treatment, but their efficacy varies.
7. Antioxidants: While antioxidants like N-acetylcysteine and sulforaphane have been explored, their efficacy remains limited.

Challenges and Suggested Approaches

Researchers face challenges in developing novel drugs for Asthma and COPD, including limited investment by pharmaceutical companies, lack of funding for basic research, and a scarcity of helpful biomarkers. To overcome these hurdles, identifying new therapeutic targets and biomarkers is crucial for better patient selection and long-term therapy monitoring.

New approaches in COPD and Asthma treatment include:

• Reversing Corticosteroid Resistance: Finding solutions to the challenge of corticosteroid resistance in patients.
• Resolving Inflammation and Aberrant Repair: Addressing inflammation and tissue repair dysregulation.
• Decelerating Aging: Focusing on strategies to mitigate the impact of aging on disease progression.

Biomarker-Driven Trial Designs

Biomarker-driven trial designs are transforming the landscape of COPD and Asthma treatments, offering a more precise and personalized approach to patient care. These innovative trial designs focus on specific biomarkers that play a crucial role in understanding the underlying mechanisms of these respiratory conditions and predicting treatment responses.

In COPD, eosinophilic inflammation is a key biomarker that helps identify patients who are more likely to respond favorably to inhaled corticosteroids (ICS) and certain biologic therapies targeting type 2 inflammation. Conversely, in non-type 2 inflammation, neutrophilia becomes a significant biomarker, guiding clinicians to explore alternative treatment strategies due to a reduced response to ICS.

For Asthma, fractional exhaled nitric oxide (FeNO) levels serve as a valuable biomarker for type 2 inflammation. Elevated FeNO levels are associated with a higher likelihood of responding well to ICS and specific biologic agents like anti-IgE and anti-IL-4R treatments. Additionally, IgE levels can indicate atopy and predict better responses to ICS and anti-IgE treatments.

Periostin emerges as a promising biomarker in both COPD and Asthma. It is associated with type 2 inflammation and airway remodeling, making it a potential indicator of treatment response to anti-IL-13 therapies in Asthmatic individuals with high periostin levels.

Summary of Clinical Trial Findings

Biomarkers are essential tools in guiding treatment decisions and assessing therapy response for Asthma and COPD. These biomarkers help in patient stratification, identifying subgroups likely to respond to specific therapies, and reducing the risk of adverse effects.

Contract Research Organizations (CROs) play a crucial role in advancing biomarker-driven research. They possess specialized expertise in biomarker discovery, validation, and analysis, accelerating the translation of research findings into clinical applications

Conclusion

In conclusion, COPD and Asthma present significant global health challenges, affecting millions of people and causing substantial morbidity and mortality. The current treatment landscape has seen advancements, but unmet needs persist. Biomarkers offer promising opportunities fo personalized treatments, while CROs play a crucial role in advancing research and developmen efforts. To address the challenges, increased investment in respiratory medicine research is essential. By fostering collaboration and innovation among stakeholders, we can strive toward better management and improved outcomes for patients living with COPD and Asthma ultimately enhancing their quality of life.

References:

• https://www.bmj.com/content/378/bmj-2021-069679
• https://erj.ersjournals.com/content/58/5/2004656