DMPK Considerations for the Development of Covalent Drugs: Insights from an IQ Assessment

Targeted covalent inhibitors (TCIs) are low-molecular-weight drugs containing a reactive warhead to inactivate target proteins. In 2023, the IQ consortium DMPK Guidelines for Targeted Covalent Drugs Workgroup surveyed 23 IQ member companies to explore knowledge around this compound class. Areas deserving special consideration included human clearance prediction and modeling approaches to predict dose. Respondents highlighted the importance of achieving sufficient warhead reactivity to engage target, while avoiding excessive off-target binding. Stability assays with glutathione (GSH) were leveraged frequently, but data interpretation challenges were reported for more complex covalent binding assays; these are typically performed in the event of safety signals. Drug binding to endogenous proteins, while not necessarily a safety concern, may result in lower recovery of total radioactivity from human mass balance studies compared to non-TCI drugs. A comparison of drug safety profiles for TCI and non-TCI did not reveal any increased safety risks for TCIs.