Quantitative Systems Pharmacology Model to Predict Target Occupancy by Bruton Tyrosine Kinase Inhibitors in Patients With B-Cell Malignancies.

Abstract

The effectiveness of Bruton tyrosine kinase (BTK) inhibitors is influenced by the level of BTK occupancy in target tissues. In randomized phase 3 studies, progression-free survival (PFS) with zanubrutinib was superior to ibrutinib, whereas acalabrutinib was noninferior to ibrutinib in previously treated chronic lymphocytic leukemia. To establish a link between numerical differences in BTK occupancy and differentiated efficacy profiles among three covalent BTK inhibitors, quantitative systems pharmacology (QSP) modeling was employed. The model was developed to describe available clinical BTK occupancy data in patients with B-cell malignancies. Simulations of BTK occupancy were conducted for various clinical scenarios (e.g., dose interruption) and for bone marrow (BM), for which routine measurements are difficult. This model describes pharmacokinetics of BTK inhibitors; intracellular concentration of BTK inhibitors in peripheral blood mononuclear cells (PBMCs), BM, and lymph nodes (LNs); binding of BTK inhibitors with BTK; and BTK turnover rate. The model was validated using available clinical BTK occupancy data. Consistent with observed clinical data, the model predicted that zanubrutinib 160 mg twice daily resulted in higher median trough BTK occupancy in PBMCs, LNs, and BM compared with ibrutinib and acalabrutinib. Although the BTK occupancy differences at trough were relatively small between the BTK inhibitors, the differences were more pronounced after dose interruption. The current work underscores the importance of maintaining high BTK occupancy at steady-state trough and during treatment interruption to ensure maximal efficacy and provides an example of combining in vitro and clinical data to model receptor occupancy in tissues where measurements are challenging.