Achieving a Low Human Dose for Targeted Covalent Drugs: Pharmacokinetic and Pharmacodynamic Considerations on Target Characteristics and Drug Attributes.

Covalent modifications of off-target biomolecules remain to be a concern for targeted covalent drugs. To guide the design of targeted covalent drugs in achieving a low human daily dose, a pharmacokinetic/pharmacodynamic (PK/PD) model was established to quantitatively evaluate target characteristics and drug properties that affect the human dose. Target characteristics, such as expression levels, turnover, and degree of inhibition relevant to efficacy, were evaluated systematically using the model. The drug properties including inactivation potency and drug clearance were also examined. Model simulations revealed the interplay of target characteristics and drug properties governed the human dose. Particularly, the extent and the duration of target inactivation meaningful to efficacy, as well as the target re-synthesis rate measured as the target turnover half-life, needed to be determined. The target information then served as a basis to inform desired drug inactivation potency and pharmacokinetic properties. The model-based approach provided a theoretical framework in achieving a low human dose of targeted covalent drugs, and the resultant strategy was successfully applied in the early stage of a Bruton's tyrosine kinase covalent inhibitor project that discovered low-dose branebrutinib. The PK/PD considerations described are also applicable to the drug design for protein degraders that share the same endpoint as targeted covalent drugs in reducing target levels. This article is protected by copyright. All rights reserved.