Targeted covalent inhibitors and protein degraders are emerging classes of molecules that offer opportunities to inhibit targets that may be difficult to do using conventional approaches. From a pharmacokinetic and pharmacodynamic (PK/PD) perspective, covalent modification and protein degradation of a target of interest share their commonality. After the intended pharmacologic action, the net result is the additional elimination of target beyond its normal removal, which leads to the reduction of target levels and the subsequent inhibition of target-associated activities. Consequently, the normal turnover of the target and degree of the target inhibition required for effective disease interventions are key questions that need to be addressed. In addition, although small molecule drugs often have excess concentrations over targets, the level of target expression can be an important factor that underpins a human efficacious dose. Understanding these aspects of target biology through PK/PD-based approaches is critical to inform the design of drug candidates on the intrinsic inactivation or degradation potency, pharmacokinetic half-life, et al. In addition, PK/PD understanding of target biology may aid dosage regimen selections in mitigating potential target toxicities associated with these compounds. In this presentation, theoretical considerations and practical examples will be provided to highlight the importance of PK/PD in guiding drug designs and dosage regimen selections for these novel classes of molecules.
Upon completion, participants will be able to understand key pharmacokinetic and pharmacodynamic considerations in the design of target covalent inhibitors and protein degraders
Upon completion, participants will be able to appreciate the value of PK/PD modeling work in guiding dosage regimen designs of a narrow therapeutic index drug
Upon completion, participants will be able to apply the learnings to guide their own work in discovery and development of novel target covalent inhibitors and protein degraders