Drug-drug interaction liabilities with BTK inhibitor TL-895

TL-895 is an orally administered protein kinase inhibitor in clinical development for the treatment of B-cell malignancies and various Other blood and autoimmune disorders. In early stages of drug development, limited data are available to assess off-target engagement and drug-drug interaction (DDI) liabilities, which may have profound effects on drug safety and efficacy. In this context, we characterized the kinase interaction profile of TL-895 and determined that the agent inhibits Btk and BMX, with more potent inhibition of BMX than Btk in a kinase assay (IC50: 0.53 versus 3.02 nM) and BRET assay (IC50: 1.6 vs 6.8 nM). We used in vitro and in vivo models to assess DDI liabilities and identified TL-895 as a substrate of the hepatic uptake transporter OATP1B1 and the enzyme CYP3A4. In vivo, co-administration of TL-895 did not increase plasma concentrations of the endogenous and xenobiotic OATP1B1 substrates chenodeoxycholic acid 24-acyl-β-D-glucuronide, pravastatin, and gilteritinib, which indicates that TL-895 is an unlikely perpetrator of OATP1B1-mediated DDIs. Consistent with hepatic microsomal studies, we found that plasma concentrations of TL-895 were increased by 1.8-fold and 4.6-fold, respectively, in male and female mice lacking all CYP3A isoforms. The pharmacokinetic profile of TL-895 was not significantly sexually dimorphic or strain dependent at drug doses producing human equivalent measures of systemic exposure. These collective findings signify an important contribution of OATP1B1 and CYP3A4 to the in vivo handling of the dual Btk/BMX inhibitor TL-895 and suggest the agent is an unlikely perpetrator of potentially deleterious DDIs in polypharmacy regimens.