Addressing health disparities through a quantitative physiological database and precision systems modeling

PROJECT SUMMARY In the realm of drug development and clinical evaluation, there is a pressing need to address the historical exclusion of underrepresented populations such as children, women, racial minorities, elderly individuals, and disease-specific groups. Regrettably, excluding these populations from drug testing results in unintended health disparities, such as disproportionate occurrences of unforeseen adverse events and reduced efficacy of already approved drugs. In the absence of diverse participation in clinical studies, a recent paradigm shift at the FDA allows for new drug application submissions to utilize physiologically-based pharmacokinetic (PBPK) modeling to describe the pharmacokinetic properties of a drug in specific populations. Although PBPK modeling is promising, two fundamental challenges make these models less applicable to underrepresented populations. First, the physiological data within current PBPK modeling tools have been derived from the reference population (Caucasian/White). These inputs also include the levels of drug metabolizing enzymes, transporters, and receptors (drug target proteins, DTPs). Second, the in vitro reagents used to model the drug-specific data are not characterized in diverse human populations, thus limiting the accuracy of in vitro in vivo extrapolation (IVIVE) predictors. In Phase I of our proposal, Precision Quantomics Inc. aims to fill these critical knowledge gaps through development of the Underrepresented Population DTP (UpDTP) database of abundance of DTPs in human liver and the creation of meticulously characterized population-specific in vitro reagents (PQ-ivR). Together, these advancements will enable the generation of key data and reagents for PBPK models that will more accurately predict drug pharmacokinetics and tissue drug concentration as surrogates of drug safety and efficacy across diverse populations. The successful completion of Phase I will serve as a proof of concept, setting a strong foundation for an expanded Phase II, where we will i) expand the UpDTP database to include other tissues, populations, and animal models for PBPK modeling to pharmaceutical and biotech organizations ii) develop custom reagents with precise scaling factors for pharmaceutical and biotech companies, and iii) validate commercially available reagents with precise scaling factors for drug testing. In conclusion, our technology has potential to advance drug development practices, elevate predictive accuracy, and ultimately contribute to improved patient care across the currently underrepresented patient populations.