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Advancing PK Studies: The Role of Microsampling in Monoclonal Antibody Therapeutics

July 17, 2024 | Admin

Introduction

Pharmacokinetic (PK) studies are fundamental in the development of monoclonal antibody (mAb) therapeutics, providing critical data on drug absorption, distribution, metabolism, and excretion. Traditional PK study methods, however, often require large sample volumes and involve extensive use of laboratory animals and discomfort for clinical study subjects, leading to ethical concerns and logistical challenges.1

Enter microsampling — a transformative technique that utilizes blood sampling with devices requiring minimal sample volumes (≤50 µL) to achieve efficient sample collection for bioanalysis. This article explores how microsampling has been shifting PK studies in mAb therapeutics, highlighting its benefits, regulatory outlook, and future potential.

A Refresher: The Benefits of Microsampling in PK Studies

Microsampling offers numerous advantages, including data quality, resource-related, and animal welfare benefits.

Reduced Animal Use: Aligning with the 3Rs: The principles of the 3Rs — Replacement, Reduction, and Refinement2 — aim to minimize animal use and harm in scientific research. Resource-wise, fewer animals are required, leading to reduced housing needs and less technician time, which translates into significant cost savings.

Microsampling directly supports these principles:

    1. Replacement: By using microsampling, researchers can often avoid using satellite animals for blood sampling, instead collecting all necessary samples from the main study animals.
    2. Reduction: The minimal volume required for microsampling means fewer animals are needed to obtain sufficient data, as individual animals can be sampled multiple times.
    3. Refinement: Microsampling techniques are less invasive and stressful for animals, reducing the need for procedures such as warming and restraint.

From an animal welfare perspective, microsampling significantly reduces blood loss, making it particularly beneficial for species with lower blood volumes, such as mice and rats. The procedure is less invasive, utilizing smaller needle gauges and capillary action pin pricks instead of full needle insertions. Overall, the reduced procedure time and less invasive nature of microsampling contribute to a less stressful experience for the animals, refining the entire blood sampling process.

Streamlined Workflows: Microsampling simplifies remote sample collection and processing for clinical studies This not only accelerates method development and sample throughput but also reduces the burden of sample shipping and cold chain storage.

Patient-Centric Clinical Trials: In clinical settings, microsampling facilitates patient-centric approaches3 by enabling at-home sampling and reducing the need for frequent clinic visits. This is particularly beneficial for populations with difficult venous access, such as children, neonates, and individuals with needle phobia. It also supports decentralized clinical trial models, which have gained prominence during the COVID-19 pandemic​.

Does Low Sample Compromise Quality? See the Evidence Supporting Microsampling in PK Studies

Recent studies have demonstrated that microsampling can produce data equivalent to traditional blood collection methods, addressing the valid concern that lower sample volumes might degrade assay quality. One notable study4 showed that microsampling techniques could generate reliable preclinical pharmacokinetic profiles for biotherapeutics from single animals. By utilizing microsampling, the researchers were able to collect serial blood samples from individual mice, reducing the number of animals used and minimizing biological variability, along with reduced study costs. This study highlights the robustness of microsampling in maintaining data integrity and quality​​.

Another key publication5 examined the use of low-volume capillary sampling in PK studies. By comparing serial and composite blood sampling methods in mice, researchers found that both yielded comparable PK profiles for two therapeutic antibodies, Denosumab and Panitumumab. Utilizing just 0.05 mL of blood, the study revealed that microsampling, combined with generic UPLC-MS/MS and Gyrolab assays, maintains high accuracy and precision, ensuring reliable PK data without sacrificing animal welfare. This finding underscores the capability of microsampling to provide accurate and reliable data, supporting its application in both preclinical and clinical PK studies​​.

Additionally, a study published in Clinical Pharmacology & Therapeutics6 investigated whether low-sampling devices can match the efficacy of traditional venipuncture methods. The study demonstrated that for crenezumab and etrolizumab, two biotherapeutics, the PK data obtained using TassoOne Plus and Neoteryx Mitra® devices were equivalent to those from conventional venipuncture. While dry blood microsampling required specific corrections for small molecules like GDC-X and hydroxychloroquine, the results still supported the viability of these methods. These findings underscore the potential for microsampling to enhance patient comfort and facilitate decentralized clinical trials without sacrificing data integrity, marking a significant advancement in patient-centric PK studies.

Regulatory Outlook for Microsampling

The regulatory landscape for microsampling is evolving, with increasing acceptance and support from international guidelines. Regulatory bodies like the FDA, EMA, and ICH have increasingly recognized the ethical and scientific advantages of reducing animal use and minimizing stress through advanced techniques like microsampling.

In 2017, updates to international guidelines7 explicitly supported the integration of microsampling into preclinical studies, addressing previous concerns about the reliability and robustness of data obtained from smaller sample volumes. These updates emphasize the need for more humane animal research practices while ensuring that the scientific integrity of PK studies is maintained or even enhanced​.

Another pivotal regulatory shift is the acceptance of data generated from microsampling in Good Laboratory Practice (GLP) toxicology studies. Historically, there was resistance due to concerns that unknown effects of microsampling might compromise assay data utilized to establish key endpoints or affect the assay’s ability to meet stringent regulatory standards. However, recent studies6 establishing the equivalence of data collected from venipuncture methods and microsampling devices have shown that microsampling has the potential to reach a broad acceptance as it is able to equivalent data in clinical studies although work to overcome bioanalytical challenges is still ongoing.

Regulatory authorities have acknowledged these findings7, leading to a broader acceptance and encouragement of microsampling techniques used in preclinical toxicology studies in official guidelines. This regulatory support is crucial as it provides a clear framework and confidence for biopharmaceutical companies to adopt microsampling, knowing that their data will be in line with regulatory expectations and can be used in regulatory submissions.

Future Considerations for Microsampling in PK Studies

To ensure the continued growth and success of microsampling in PK studies, several considerations must be addressed:

  • Standardization: Developing standardized protocols for microsampling, sample processing, and bioanalysis to ensure consistency and reliability across studies.
  • Technological Integration: Leveraging advanced bioanalytical platforms, such as the Gyrolab® platform, to enhance the efficiency and accuracy of microsample analysis.
  • Regulatory Engagement: Continued dialogue with regulatory bodies to address emerging challenges and ensure the regulatory framework supports innovation in microsampling.

Conclusion

Microsampling is poised to revolutionize sample collection for preclinical and clinical PK studies for mAb therapeutics, offering significant benefits in terms of animal welfare, patient convenience, data quality, and logistical efficiency. As regulatory acceptance grows and technological advancements continue, microsampling will play an increasingly vital role in drug development.

By integrating microsampling with advanced bioanalytical platforms that utilize very low sample volumes like the Gyrolab® platform, researchers can achieve new levels of efficiency and precision in their studies.

Want More Efficient Workflows? Microsampling and the Gyrolab® Platform

The Gyrolab® platform from Gyros Protein Technologies is at the forefront of revolutionizing bioanalytical workflows with its groundbreaking technology. The Gyrolab platform automates immunoassays at a nanoliter scale, making it the perfect complement to microsampling techniques. By utilizing nanoliter microfluidics, the Gyrolab system offers efficient immunoassay workflows, high-quality data, and enhanced productivity in bioanalysis PK studies.

How Microsampling Complements Gyrolab Technology

  • Efficiency: The Gyrolab platform’s miniaturized ELISA technology allows for automated nanoliter-scale immunoassays, minimizing manual pipetting and saving valuable time.
  • Low Sample Volume: The system’s ability to operate with low sample volumes is ideal for microsampling, reducing the need for large blood draws.
  • High Reproducibility: The microfluidic immunoassay technology ensures consistent, high-quality data with broad dynamic ranges.
  • Streamlined Workflows: Gyrolab’s affinity flow-through format eliminates the need for incubations, reducing assay run times to about an hour with fully unattended operation.

The Gyrolab suite, including the Gyrolab xPand and Gyrolab xPlore systems, Bioaffy CDs, kits and solutions, and custom assay services, empowers scientists to maximize productivity and make data-driven decisions swiftly.

For over 20 years, Gyros Protein Technologies has been a trusted leader in the industry, providing innovative solutions that accelerate immunoassay workflows and enable rapid, data-driven decision-making.

References

  1. Clemence, M. “Public attitudes to animal research in 2018”. Ipsos. 14 May 2019, https://www.ipsos.com/en-uk/public-attitudes-animal-research-2018.
  2. “The 3Rs”. https://www.nc3rs.org.uk/who-we-are/3rs
  3. National Institutes of Health. “NIH begins study to quantify undetected cases of coronavirus infection”. 10 April 2020, https://www.nih.gov/news-events/news-releases/nih-begins-study-quantify-undetected-cases-coronavirus-infection
  4. Joyce A, Wang M, et al. “One mouse, one pharmacokinetic profile: quantitative whole blood serial sampling for biotherapeutics”. Pharm Res. 2014 Jul;31(7):1823-33. doi: 10.1007/s11095-013-1286-y. Epub 2014 Jan 24.
  5. Mano Y, Kita K, et al. “Generic UPLC-MS/MS and Gyrolab assays with blood microsampling for pharmacokinetic assessments of therapeutic antibodies in mice.” Journal of Pharmaceutical and Biomedical Analysis 241, 15 April 2024, 115993.
  6. Mandlekar S, Sutaria DS, et al. “Evaluation of Patient-Centric Sample Collection Technologies for Pharmacokinetic Assessment of Large and Small Molecules.” Clinical Pharmacology & Therapeutics. 26 April 2024 https://doi.org/10.1002/cpt.3272
  7. European Medicines Agency (2017). ICH Guideline S3A: Note for guidance on toxicokinetics: the assessment of systemic exposure in toxicity studies - questions and answers. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-s3a-note-guidance-toxicokinetics-assessment-systemic-exposure-toxicity-studies_en.pdf

 
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