Clint Rosenfeld, PhD, Senior Director, DMPK
Jocelyn Mielke, BA, LAT, Associate Kinetic Scientist
If you have completed pharmacokinetic (PK) screening and the lead optimization process, and you think you’re ready to take your molecule through the drug development process, there are several factors that need to be considered. Certain fundamental questions should be answered to address some critical PK aspects of the selected compound(s). At MPI Research, we always recommend conducting “A Gap Analysis” to identify deficiencies and provide an approach moving forward that mitigates risk and accounts for unknown factors that may require consideration.
Following candidate recommendation for development, review the discovery data and ask these fundamental questions
- Is the test article(s) used in the same form as the test article(s) selected for development? When looking at the discovery PK data, is the compound analyzed in those studies in the same form (salt, free base, formulation, tox batch, etc.) as what you will take into toxicity studies? If the answer is yes, the PK data previously obtained should be reliable and reproducible information that can be used for predictions on dose and time point selections. If the answer is no, consider running additional studies to support the gaps identified, such as a non-GLP, bridging PK study with the large animal species to be used in development.
- Is there an understanding of deviation from linearity in the PK of the selected compounds (dose levels approaching the magnitude to what will be used in safety studies)? If you only have PK data at low-dose levels, additional studies may be required in order to obtain information on deviating from linearity for appropriate dose selection in pivotal studies. If you have PK data at higher dose levels and linearity has been determined (i.e., absorption and clearance are constant across the range), these data can be utilized for selecting appropriate doses for subsequent required studies. A fundamental understanding of the linearity of the lead compounds selected is something you’ll want to gain prior to going into development.
- Have repeat-dose PK data been evaluated (i.e., 7-day dose-range finder)? Is there an understanding of metabolic changes (induction and/or accumulation) following repeated administration? If one of these studies hasn’t been conducted, now would be the time to consider it in order to avoid potential pitfalls in longer term studies and identify the appropriate dose levels to use in pivotal studies.
- Is there a fundamental understanding of food effect for orally administered compound(s)? Do you know in your large animal species whether or not food has an impact on exposure? This question is applicable if gastric pH is a factor in absorption of the selected compound(s). For example, if the solubility of your compound is such that more is free at a lower pH level, you’ll find that if you give it to a fasted dog, you can increase the level of variability and reduce overall systemic exposure. If animals are fed prior to administration, the pH level in the animal’s stomach is normalized, study variability may be reduced and exposure will potentially be optimized. Ensuring the appropriate fasted/fed status in animals prior to administration can reduce variability and provide more reliable exposure data. If you don’t know the answer to this question, consider running a food effect PK study prior to safety study planning and execution.
- Have the appropriate time points been selected? The appropriate time points to be used for exposure assessment should be determined prior to conducting/planning studies to define safety. ICH S3A guidance on the assessment of systemic exposure in toxicity studies states, “In each study the number of time points should be justified on the basis that they are adequate to estimate exposure toxicity studies, from pilot of dose range-finding studies, from separate studies in the same model or in other models allowing reliable extrapolation.” This information can be determined from pilot/PK studies utilizing a robust sampling scheme and analyzing the data to determine the best time points to be used for determination of systemic exposure and to minimize any potential impact for future pivotal studies. If this information has not been obtained, additional studies may be necessary to justify the number of time points being used to estimate exposure in toxicity studies.