Predicting kinase target inhibition level for efficacy in rheumatoid arthritis: A translational approach based on
Rui Li1, Roger Gifford2, Peter Symanowicz2
1Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc, Cambridge, Massachusetts.
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 (IAVG). 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 IAVG required for efficacy was generally consistent between humans and rodents. Overall, the IAVG-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, IAVG-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.
Insights
Establishing the correct dose for new rheumatoid arthritis therapies is crucial. This study introduces a new method using average target inhibition (IAVG) to predict effective doses in humans from preclinical rodent data.
Area of Science:
- Pharmacology
- Rheumatology
- Drug Development
Background:
- Determining efficacious doses for novel therapies, particularly small-molecule kinase inhibitors for rheumatoid arthritis (RA), is challenging during preclinical development.
- Predicting the required target inhibition level for efficacy from preclinical data is a key unmet need.
- Existing methods often fail to accurately translate preclinical findings to human therapeutic doses.
Purpose of the Study:
- To develop a translational approach for predicting the lowest efficacious target inhibition level in rheumatoid arthritis (RA) patients.
- To establish a method for estimating efficacious doses of kinase inhibitors based on preclinical rodent data.
- To compare a novel average inhibition level (IAVG) approach with classic methods for predicting drug efficacy.
Main Methods:
- Utilized collagen-induced arthritis rodent models and human patient data for kinase inhibitors (tofacitinib, zimlovisertib, and others).
- Calculated and compared average inhibition levels (IAVG) across different doses and species.
- Analyzed classic pharmacokinetic/pharmacodynamic (PK/PD) approaches, including exposure above IC50 and IC90.
Main Results:
- The lowest average inhibition level (IAVG) required for efficacy was found to be consistent between rodents and humans.
- The IAVG-based approach demonstrated better alignment between rodent and human efficacy compared to traditional methods.
- This novel approach showed greater universal applicability for predicting efficacious doses.
Conclusions:
- The proposed IAVG-based rodent-to-human translation is a valuable tool for predicting target inhibition levels and efficacious doses for future rheumatoid arthritis kinase inhibitors.
- This translational approach can improve the accuracy of preclinical dose selection for targeted therapies.
- The IAVG method holds potential applicability for other small-molecule targeted therapies beyond RA treatment.
