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Preclinical  in vivo  studies form the cornerstone of drug development and translation, bridging  in vitro  experiments with first-in-human trials. However, despite the utility of animal models, translation from the bench to bedside remains difficult, particularly for biologics and agents with unique mechanisms of action. The limitations of these animal models may advance agents that are ineffective in the clinic, or worse, screen out compounds that would be successful drugs. One reason for such failure is that animal models often allow clinically intolerable doses, which can undermine translation from otherwise promising efficacy studies. Other times, tolerability makes it challenging to identify the necessary dose range for clinical testing. With the ability to predict pharmacokinetic and pharmacodynamic responses, mechanistic simulations can help advance candidates from  in vitro  to  in vivo  and clinical studies. Here, we use basic insights into drug disposition to analyze the dosing of antibody drug conjugates (ADC) and checkpoint inhibitor dosing (PD-1 and PD-L1) in the clinic. The results demonstrate how simulations can identify the most promising clinical compounds rather than the most effective  in vitro  and preclinical  in vivo  agents. Likewise, the importance of quantifying absolute target expression and antibody internalization is critical to accurately scale dosing. These predictive models are capable of simulating clinical scenarios and providing results that can be validated and updated along the entire development pipeline starting in drug discovery. Combined with experimental approaches, simulations can guide the selection of compounds at early stages that are predicted to have the highest efficacy in the clinic.

Predictive Simulations in Preclinical Oncology to Guide the Translation of Biologics