As sponsors transition their programs from preclinical animal Tox studies to human clinical trials, sponsors turn to AIT Bioscience (AITB) to help understand the potential issues that may arise with their bioanalytical PK assays. In Contract Pharma’s October issue, AITB tackles this topic to highlight where some unexpected challenges and expenses can arise (Robust Assay Designs) and how these can be overcome.
Key challenges for small molecule therapeutics include:
- Wide assay range in preclinical studies vs. assay sensitivity in clinical studies
- Tox studies entail every higher dosing levels to determine maximum tolerated and toxic dose levels.
- Clinical studies typically have a much narrower dosing range and focus is often on trough levels of drug
- Assay specificity due to matrix variability – Tox species are typically homogeneous so minimal variability between animals, but the opposite is true in human clinical studies
- Identifying a suitable internal standard
To mitigate these issues AITB advises the use of a stable isotope labeled internal standard. Read our case study on this topic. Regarding matrix variability, AITB recommends screening multiple lots of blank matrix (typically at least 10 individual lots).
In large molecule therapeutic programs, matrix variability poses a bigger issue because there are no internal standards to normalize assay response. Thus, assay specificity is a key parameter, and we spend a considerable amount of time to understand the potential impact on the assay. This process is particularly complex when moving into later stage clinical studies where diseased subjects are enrolled and ligand binding assays can be impacted.
The use of commercial critical reagents (not specific to the biotherapeutic drug) can pose its own problems as well. Variability in the quality of these critical reagents can plague a long-term clinical study where the assay may be run multiple times by different analysts over the course of several years.
The magic bullet for ligand binding assays are drug specific critical reagents. They can mitigate matrix variability issues, facilitate more sensitive assays, and reduce the lot to lot variability issues seen with commercial reagents.
For sponsors, understanding how a contract lab will take these issues into account to balance cost of reagents, cost of assay development, with assay quality will help ensure both short and long-term success in PK studies.
Have questions on your program? Contact us to talk with our experts and see how we can help you.