The Role of Pharmacokinetics (PK) in Drug R&D
Pharmacokinetics (PK) is defined as the study of the fate of a new therapeutic entity (NTE) after it is administered into the body of animals or humans. It involves understanding how the drug is absorbed, distributed, metabolized, and eliminated (ADME). Essentially, PK helps determine how long the drug remains in the body, how it acts on its target, and how it is eventually removed.
To understand how a drug may impact the body, measuring its levels at various time points post-administration in different animal species is essential to ensure ideal efficacy with minimal toxicity and optimal drug dose when stepping into first-in-human (FIH) clinical studies. PK studies typically start with rodents (mouse, rat) and move up to larger mammals like for example: non-human primates (NHP), before the drug enters clinical development in humans. This progression ensures a comprehensive understanding of the drug’s behavior across different biological systems.
This blog captures a recent internal conversation between experts from our team, during which they explore the intricacies of PK studies, and the methodologies involved in ensuring accurate drug measurement, from early development through method qualification and validation.
Streamlining PK Studies: Solutions for Preclinical and Clinical Drug Testing
Conducting PK studies involves measuring circulating drug levels over time in easily sampled biological fluids, such as blood or urine, to predict its concentration at receptor sites. This requires developing precise quantification methods, which, for New biological entities (NBE), predominantly rely on immunoassays using specific reagents, primarily antibodies (Abs). These critical reagents enable accurate measurement within complex biological matrices such as plasma, serum, urine or CSF.
Our team at KCAS Bio is proficient in guiding clients through the entire PK study process, from preclinical animal studies to clinical trials. In the early stages, clients approach us when they are still testing different NBE candidates for their promising target and have not generated specific reagents for each candidate. This is where our experience in developing generic PK studies proves highly beneficial.
Developing PK Methods: ensuring standards of accuracy and reliability
A PK method involves coating capture reagents on a plate, a saturation step to limit non-specific interactions, adding test samples, controls and calibrators, and a detection step, often with a drug-specific antibody. The development of a reliable PK method, that can accurately measure drug concentration, entails several essential steps.
Matrices, typically serum or plasma, can cause interferences in the assay. This matrix effect can arise from binding partners, such as circulating targets, FcRn, or anti-drug antibodies (ADA), or from non-specific interactions with major plasma proteins such as albumin or immunoglobulins. To mitigate these interferences, we can optimize the concentrations of critical reagents, and sample diluents as well as increase sample MRD (minimal required dilution).
Developing the most reliable method requires several optimization steps and the expertise of a dedicated scientific team. This is where the added value of our team of scientists truly shines, ensuring that we achieve the highest standards of accuracy and reliability.
From Development to Validation: Achieving Method Reliability and Regulatory Compliance
Once method development is robust and finalized, including any adjustments in operators, critical reagents, or minor parameter changes (such as incubation time or temperature), we transfer the method to the validation/testing team. This team will then manage the qualification or validation process. This process follows bioanalytical method validation (BMV) guidelines (FDA, EMA, ICH M10)1,2 and involves implementing all necessary controls and procedures to ensure the method’s reliability and its accuracy and precision in quantifying the test item of interest.
We benefit greatly from our organizational structure, which fosters our development and validation teams working hand in hand: validation/testing team can consult with the development team to resolve any issues, ensuring that previously encountered problems are addressed effectively. The validated methods are then used in preclinical toxicology studies under GLP (Good Laboratory Practice) conditions and in clinical trials in compliance with GCP (Good Clinical Practice) and GCLP (Good Clinical Laboratory Practice) standards.
With dedicated teams handling operations, quality control (QC), and quality assurance (QA), we offer comprehensive support and data review throughout the entire preclinical and clinical development process. Our QC team is highly skilled and actively engages with operational teams to resolve any issues. Additionally, our QA team rigorously reviews procedures, regularly conducts audits of different study phases, and collaborates with the operational team to maintain high standards of quality throughout all steps. This continuous synergy between teams, including during method validation and testing, ensures that any problem is promptly addressed and resolved.
Customer Collaboration and Tailored Solutions
As mentioned above, our approach is highly collaborative, extending beyond internal interactions. We strongly believe that working closely with our clients to understand their specific needs and challenges is key for success. This partnership allows us to tailor our methodologies precisely to their requirements, whether for generic, in the early-stage or specific PK assays for more advanced (pre)clinical stages.
Combining the knowledge that our clients have of their drug, the biology of their target, and their indication, with our expertise in developing and troubleshooting PK methods, based on our comprehensive technological platforms, we can swiftly select the right tools to meet Sponsor’s specifications. Another major advantage we offer is our ability to adapt methods developed for one species to another, saving time and costs.
We have extensive expertise with various types of NBEs, including proteins, peptides, antibody-based therapeutics. Our significant experience in developing these methods allows us to leverage a range of strategies to optimize and advance our methodologies.
At the core of our approach, we strive to maintain close communication, transparency, proactive, solution-oriented mindset and flexibility throughout the method development process with regular meetings and data sharing. If issues arise, we don’t hide them; instead, we openly address them and offer solutions. Troubleshooting is a crucial aspect of our work: even when challenges occur, we focus on providing cost-effective solutions without unnecessary additional expenses. We aim to optimize both costs and time.
Future Directions
Looking ahead, we are enhancing our traceability and data management capabilities by implementing the Watson LIMS (Laboratory Information Management System). This system will streamline the analysis and reporting processes, ensuring even greater accuracy and efficiency in our PK studies.
PK analysis plays a foundational role in drug R&D. Our comprehensive approach, advanced methodologies, and client-focused strategies position us as leaders in the field, ready to tackle the most challenging PK studies and drive forward the next generation of pharmaceuticals.
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