Semi-mechanistic PK/PD modeling and simulation of irreversible BTK inhibition to support dose selection of tirabrutinib in subjects with RA

Tirabrutinib is an irreversible, small-molecule Bruton's tyrosine kinase (BTK) inhibitor, which was approved in Japan (VELEXBRU® ) to treat B-cell malignancies and is in clinical development for inflammatory diseases. As an application of model-informed drug development, a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for irreversible BTK inhibition of tirabrutinib was developed to support dose selection in clinical development, based on clinical PK and BTK occupancy data from two Phase 1 studies with a wide range of PK exposures in healthy volunteers and in subjects with rheumatoid arthritis (RA). The developed model adequately described and predicted the PK and PD data. Overall, the model-based simulation supported a total daily dose of at least 40 mg, either QD or BID, with adequate BTK occupancy (>90%) for further development in inflammatory diseases. Following the PK/PD modeling and simulation, the relationship between model-predicted BTK occupancy and preliminary clinical efficacy data was also explored and a positive trend was identified between the increasing time above adequate BTK occupancy and better efficacy in treatment for RA by linear regression.