Evaluation of the Cytochrome P450 3A and P-glycoprotein Drug-Drug Interaction Potential of Futibatinib

by Selleckchem | Sep 01 2023

Futibatinib, a selective, irreversible fibroblast growth factor receptor 1-4 inhibitor, is being investigated for tumors harboring FGFR aberrations and was recently approved for the treatment of FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. In vitro studies identified cytochrome P450 (CYP) 3A as the major CYP isoform in futibatinib metabolism and indicated that futibatinib is likely a P-glycoprotein (P-gp) substrate and inhibitor. Futibatinib also showed time-dependent inhibition of CYP3A in vitro. Phase I studies investigated the drug-drug interactions of futibatinib with itraconazole (a dual P-gp and strong CYP3A inhibitor), rifampin (a dual P-gp and strong CYP3A inducer), or midazolam (a sensitive CYP3A substrate) in healthy adult participants. Compared with futibatinib alone, coadministration of futibatinib with itraconazole increased futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 51% and 41%, respectively, and coadministration of futibatinib with rifampin lowered futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 53% and 64%, respectively. Coadministration of midazolam with futibatinib had no effect on midazolam pharmacokinetics compared with midazolam administered alone. These findings suggest that concomitant use of dual P-gp and strong CYP3A inhibitors/inducers with futibatinib should be avoided, but futibatinib can be concomitantly administered with other drugs metabolized by CYP3A. Drug-drug interaction studies with P-gp-specific substrates and inhibitors are planned.

Comments:

Futibatinib is an investigational drug that has shown promise as a selective, irreversible inhibitor of fibroblast growth factor receptors 1-4 (FGFR1-4). It is being studied for its potential use in treating tumors that have FGFR aberrations. Recently, futibatinib has received approval for the treatment of intrahepatic cholangiocarcinoma (a type of liver cancer) that is positive for FGFR2 fusion or rearrangement.

In vitro studies have provided insights into the metabolism of futibatinib. These studies have identified cytochrome P450 (CYP) 3A as the primary CYP isoform involved in the metabolism of futibatinib. Furthermore, it has been suggested that futibatinib is likely a substrate for P-glycoprotein (P-gp) and can also inhibit its activity. Time-dependent inhibition of CYP3A by futibatinib has also been observed in these studies.

Phase I studies have been conducted to investigate the potential drug-drug interactions of futibatinib with other medications in healthy adult participants. Specifically, the interactions of futibatinib with itraconazole (a dual P-gp and strong CYP3A inhibitor), rifampin (a dual P-gp and strong CYP3A inducer), and midazolam (a sensitive CYP3A substrate) were evaluated.

The results of these studies showed that coadministration of futibatinib with itraconazole increased the mean peak plasma concentration and area under the plasma concentration-time curve of futibatinib by 51% and 41%, respectively. On the other hand, coadministration of futibatinib with rifampin decreased the mean peak plasma concentration and area under the plasma concentration-time curve of futibatinib by 53% and 64%, respectively. However, when midazolam was coadministered with futibatinib, it had no significant effect on the pharmacokinetics of midazolam compared to when midazolam was administered alone.

Based on these findings, it is recommended to avoid concomitant use of futibatinib with dual P-gp and strong CYP3A inhibitors or inducers. Such combinations could potentially alter the plasma concentrations and exposure of futibatinib, affecting its efficacy and safety. However, futibatinib can be safely administered with other drugs that are metabolized by CYP3A. Further drug-drug interaction studies are planned to explore the interactions of futibatinib with P-gp-specific substrates and inhibitors, providing additional information for its safe and effective use in combination therapies.