Development of a Time-based Drug Screening Platform for Improved Clinical Translation

In 2022, the average cost for a single drug’s development increased by 15%, reaching $2.3 billion. In drug development, oncology has the highest attrition rate with 95% of new drugs failing Phase 2 clinical trials alone. Consequently, innovative approaches are needed to assess clinical utility prior to proceeding with human trials. Current drug development follows the theory that “Best Potency = Best Drug” which is a concentration-centric paradigm focused on optimizing drug-target interaction (K _d ) to improve the concentration of drug necessary to elicit its therapeutic effect ( IC ₅₀ ). However, both drug concentration and exposure time contribute to clinical efficacy, yet most laboratory studies focus on IC ₅₀ alone. This manuscript characterizes drug potency and kinetics of ten oncology drugs in three different cancer cell lines and integrates in vivo pharmacokinetic-pharmacodynamic models to identify how these parameters relate to real-world clinical outcomes. Our analyses revealed that C _max normalization is necessary for concentration response data as IC ₅₀ alone does not account for drugs that are studied at sub-therapeutic concentrations. Additionally, the temporal effect of drug efficacy varies between cell lines and dose, where some drugs are unable to overcome the proliferation rate of the cells to induce a decrease in disease progression. This work aims to enhance the design and implementation of drug regimens by understanding the time-dependence of clinical efficacy and cytotoxicity.