A Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Model for Covalent Bruton Tyrosine Kinase Inhibitor TL-895
Authors: Taylor Adekemi , Zhao Janet , Allard Martine , Kendrick Racheal , Pheng Leng Hong , Krejsa Cecile , Slatter J. Greg 
Published: February 2025

Background: TL-895 is a highly potent, selective, covalent Bruton tyrosine kinase (BTK) inhibitor under development for treatment of patients with allergic inflammatory disorders and hematologic diseases. A healthy volunteer (HV) population pharmacokinetic/pharmacodynamic (PopPK/PD) model was developed from richly sampled PK and BTK target occupancy (BTKTO) profiles to aid dose regimen selection for disease indications with various BTK resynthesis rates. Methods: The PopPK model was based on two HV studies: MS200662-0017 (N&#3f17, 300 mg dose with food), and TL-895-204 (N&#3f26; 150 mg dose with food ± omeprazole). An irreversible turnover model described BTKTO PD. Steady-state BTKTO at trough and duration of optimal target occupancy, defined as BTKTO >95&#37; (Dur95), were simulated for various dose regimens and BTK resynthesis rates in target cells. Nonlinear mixed-effects modeling was used and evaluated based on parameter precision, standard diagnostics and visual predictive checks. Results: A two-compartment model with sequential zero-order release and first-order absorption, absorption lag time, and linear elimination, captured the PK data. The apparent clearance was 221.0 L/hour (h) (3.3&#37; relative standard error [RSE]) with an apparent central volume of distribution of 77.2 L (9.8&#37; RSE). Covariate analysis indicated that omeprazole decreased TL-895 bioavailability by 50&#37;. Lower TL-895 exposure with omeprazole gave adequate PD dynamic range to discern the saturation kinetics of BTKTO. The PD model indicated a first-order BTK degradation rate constant of 0.0126h-1 (4.8&#37; RSE) and second-order irreversible binding rate constant of 0.0127 (ng/ml)-1 h-1 (24&#37; RSE). Model performance was acceptable. PK and PD were simulated using the estimated BTK HV resynthesis half-life (55.0 h). Following twice daily (BID) dosing, BTKTO rapidly saturated, with limited gains in trough BTKTO at doses above 150 mg BID, aligning with a covalent mechanism of action. After administration of TL-895 at 150 mg BID and 300 mg once daily (QD), trough BTKTO was 93.5&#37; and 86.4&#37;, respectively. Median Dur95 was 9 h of each 12-h interval at 150 mg BID, and 10 h of each 24-h interval at 300 mg QD. Higher trough BTKTO and longer overall duration of BTK occupancy were clear benefits of BID dosing. For faster BTK resynthesis, which might be expected in activated or proliferating cells, simulations predicted decreased Dur95 within each dose interval. Conclusions/Summary: The TL-895 PopPK/PD model showed rapid target saturation and only small gains in trough BTKTO at doses above 150 mg BID. BID dosing increased duration of optimal target coverage by ~2-fold over QD dosing. Exposure-response (E-R) relationships of covalent BTK inhibitors can be flat due to near-complete target saturation at clinically active doses. The TL-895 PopPK/PD model is a useful addition to E-R modeling to identify dose regimens that achieve optimal BTK target coverage at different BTK resynthesis rates.Citations: N/A