Data from Drug–Drug Interaction Liabilities with BTK Inhibitor TL-895

Abstract 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 the 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 Bruton’s tyrosine kinase (BTK) and bone marrow kinase on chromosome X (BMX), with more potent inhibition of BMX than BTK in a kinase assay (IC₅₀: 0.53 vs. 3.02 nmol/L) and a bioluminescence resonance energy transfer (BRET) assay (IC₅₀: 1.6 vs. 6.8 nmol/L). 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, coadministration 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- 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. Significance: TL-895 is an investigational second-generation BTK inhibitor for the treatment of B-cell malignancies. We found that TL-895 undergoes hepatocellular uptake by OATP1B-type transporters in advance of extensive CYP3A-mediated metabolism but is unlikely to perpetrate pharmacokinetic DDIs that could compromise drug safety in the context of polypharmacy regimens.