Integrated Population Pharmacokinetic, Pharmacodynamic, and Safety Analyses to Inform Dosage Selection in the Clinical Development of the ATR Inhibitor Tuvusertib

This study demonstrates how a model-informed, totality-of-evidence approach was used to select the optimal clinical dose of the ATR inhibitor tuvusertib in patients with advanced solid tumors. By integrating pharmacokinetics (PK), pharmacodynamics (PD), safety, and early efficacy data from preclinical studies and a Phase I trial, researchers developed quantitative models to characterize exposure–response relationships and treatment-related toxicity.

The analysis identified anemia as the key dose-limiting toxicity and showed that intermittent dosing schedules could mitigate this risk while maintaining antitumor activity. Modeling and simulation supported 180 mg once daily (2 weeks on / 1 week off) as the recommended dose for expansion, balancing efficacy and safety, with lower doses providing a potential safety margin for further evaluation.

Overall, the study highlights the value of integrated quantitative pharmacology and model-informed drug development (MIDD) in enabling data-driven dose selection, reducing uncertainty, and supporting more efficient early-phase oncology development.