Drug-Drug Interaction Liabilities with BTK Inhibitor TL-895.

Area of Science:

• Pharmacology
• Drug Metabolism and Pharmacokinetics
• Oncology

Background:

• Limited early-stage data exists for drug-drug interaction (DDI) liabilities of novel therapeutics.
• Understanding off-target engagement and transporter/enzyme interactions is crucial for drug safety and efficacy.

Purpose of the Study:

• To characterize the kinase interaction profile of TL-895.
• To assess the drug-drug interaction (DDI) liabilities of TL-895 as a substrate of OATP1B1 and CYP3A4.

Main Methods:

• Kinase inhibition assays (IC50) and BRET assays were used to determine enzyme inhibition.
• In vitro and in vivo models were employed to evaluate DDI potential with OATP1B1 and CYP3A4.
• Pharmacokinetic studies were conducted in CYP3A-null mice to assess enzyme-mediated interactions.

Main Results:

• TL-895 potently inhibits both Bruton's tyrosine kinase (BTK) and Bmx, with greater potency against Bmx (IC50: 0.53 nM).
• TL-895 is identified as a substrate for the hepatic transporter OATP1B1 and the enzyme CYP3A4.
• TL-895 did not increase plasma concentrations of OATP1B1 substrates, indicating it's an unlikely DDI perpetrator via this transporter.
• CYP3A4 inhibition led to increased TL-895 plasma concentrations in CYP3A-null mice, confirming CYP3A4's role in its metabolism.

Conclusions:

• TL-895 is a dual BTK/BMX inhibitor with a defined kinase interaction profile.
• OATP1B1 and CYP3A4 significantly contribute to the in vivo disposition of TL-895.
• TL-895 is unlikely to be a perpetrator of clinically significant OATP1B1-mediated DDIs, supporting its potential use in polypharmacy regimens.