Predicting kinase target inhibition level for efficacy in rheumatoid arthritis: A translational approach based on collagen-induced arthritis rodent studies

Abstract

Setting a clinically efficacious dose in the preclinical stage is an important but challenging task in developing new therapies, including small-molecule kinase inhibitors for rheumatoid arthritis (RA). Besides pharmacokinetics and potency, another key component in determining the efficacious dose of a small molecule targeted therapy is the target inhibition level required for efficacy, which few established approaches can predict based on preclinical data. Using collagen-induced arthritis rodent data, we aimed to establish a translational approach in predicting the lowest efficacious target inhibition level in patients with RA, assuming that similar levels of target inhibition are required for efficacy in both patients and animal models. Target inhibition levels of tofacitinib, zimlovisertib, and 3 literature kinase inhibitors at efficacious and inefficacious doses were compared between patients and rodents using a new approach based on average inhibition level (I_AVG). For comparison purposes, classic approaches based on average, maximal, and minimal exposures and durations with exposure above IC₃₀, IC₅₀, IC₇₀, and IC₉₀ are also included in our analysis. We found that the lowest I_AVG required for efficacy was generally consistent between humans and rodents. Overall, the I_AVG-based approach led to a better alignment between rodent and human efficacy and is more universally applicable than other approaches. For future kinase inhibitors in discovery or development, I_AVG-based rodent-to-human translation can be used to identify the target inhibition level required for efficacy and corresponding efficacious dose in patients with RA. SIGNIFICANCE STATEMENT: Identifying the target inhibition level required for clinical efficacy in the preclinical stage is important in developing new therapies. However, there are few established approaches aiming to predict this level based on preclinical data. Using data from kinase inhibitors for rheumatoid arthritis, this study proposed a rodent-to-human translation approach. The established translation helps to predict the efficacious inhibition level and corresponding efficacious dose for future kinase inhibitors for rheumatoid arthritis. The approach may also be applicable to other small-molecule targeted therapies.

Keywords: Animal models; Collagen-induced arthritis; Human dose prediction; Pharmacokinetic-pharmacodynamic modeling; Rheumatoid arthritis; Translational pharmacology.