Identification of oncology pharmacokinetic drivers through in vitro experiments and computational modeling

Drug discovery balances many factors as it identifies compounds for clinical testing, including compound efficacy, safety, pharmacokinetic (PK) properties, commercial feasibility, competitive positioning, and organizational pressures to move quickly with limited knowledge. When considering target engagement within clinically acceptable dosing constraints, design elements often balance potency requirements against the required extent of target engagement, which subsequently inform the PK design criteria (e.g. absorption and half-life considerations). Hence, an early understanding of the magnitude and duration of target engagement can focus design teams by providing well defined design criteria. To this end, an in vitro target engagement assay has been developed to bin targets and compounds by the type of target engagement profile required for efficacy (cellular anti-proliferation). This in turn directionally informs on the required concentration profile most aligned with the efficacy readout, bucketing results into three primary categories that drive efficacy: high transient concentrations, average concentrations, and threshold concentrations. This manuscript will outline the methodology developed for this early target coverage assessment and provide examples with selected compounds spanning molecularly targeted and cytotoxic oncology small molecules.