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Purpose Fenebrutinib (GDC-0853), a Bruton's tyrosine kinase (BTK) inhibitor was investigated in a Phase 2 clinical trial in patients with rheumatoid arthritis (RA). Our aim was to apply a model-informed drug development (MIDD) approach to examine the totality of available clinical efficacy data. Methods Population pharmacokinetics (popPK) modeling, exposure-response (E-R) analysis, and model-based metaanalysis (MBMA) of fenebrutinib were performed based on the Phase 2 data. Results PopPK of fenebrutinib after oral administration was described using a 3-compartment model with linear elimination and a flexible absorption transit compartment model. Healthy subjects had a 52% higher apparent clearance than patients. E-R analyses based on longitudinal ACR20, ACR50, and ACR70 and DAS28 (CRP) data modeled fenebrutinib effect with an E max function, and an efficacy plateau was achieved within the exposure range obtained in the Phase 2 clinical trial. Based on literature data, a summary-level clinical efficacy database was constructed, and MBMA determined ACR20, ACR50, and ACR70 responder rates in the placebo and adalimumab arms of the Phase 2 clinical trial were found to be consistent with historical data for these treatments. Conclusions Our multi-pronged approach applied MIDD to maximize knowledge extraction of efficacy data and enabled robust interpretation from a Phase 2 clinical trial. KEY WORDS Bruton's tyrosine kinase (BTK) inhibitor. exposure-response. model-based meta-analysis. population pharmacokinetics. rheumatoid arthritis ABBREVIATIONS AUC Area under the concentration-time curve BTK Bruton's tyrosine kinase CL/F Apparent clearance C max Maximum concentration C min Trough concentration CRP C-reactive protein DAS28 Disease Activity Score with 28-joint counts EBE Empirical Bayes estimates E-R Exposure-response F1 Relative extent of absorption FOCE-I First order conditional estimation with interaction MBMA Model-based meta-analysis MIDD Model-informed drug development MTT Mean transit time MTX Methotrexate NLME Non-linear mixed effects NTR Number of transit compartments pcVPC Prediction-corrected visual predictive check PD Pharmacodynamic The original version of this article was revised: The article was published with an incomplete title. The complete title is "Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis".

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