Dual P-glycoprotein and cytochrome P450 (CYP) 3A inhibitors or inducers should not be used together with futibatinib, a recently approved irreversible fibroblast growth factor receptor (FGFR) 1–4 inhibitor, to treat intrahepatic cholangiocarcinoma (CCA), according to a new study published in the journal Clinical Pharmacology in Drug Development.
“But futibatinib can be concomitantly administered with other drugs metabolized by CYP3A,” the researchers said.
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Previous research has shown that CYP3A is the major CYP in futibatinib metabolism and that the drug is most probably a P-glycoprotein (P-gp) substrate and inhibitor. It has also been shown that futibatinib can inhibit CYP3A in a time-dependent manner, the researchers noted.
In phase 1 clinical trials, the drug-drug interactions of futibatinib with itraconazole, rifampin, and midazolam have been tested in healthy volunteers.
The results of these trials have shown that futibatinib plus itraconazole increased the mean peak plasma concentration of futibatinib by 51% and the area under the plasma concentration–time curve by 41% compared to futibatinib alone.
On the other hand, the coadministration of futibatinib together with rifampin lowered these values by 53% and 64%, respectively.
When futibatinib was given together with midazolam the pharmacokinetics of midazolam were not affected compared to when it was used on its own.
Itraconazole and rifampin are both dual P-gps. Itraconazole is also a strong inhibitor of CYP3A while rifampin is a strong CYP3A inducer. Finally, midazolam is a sensitive CYP3A substrate.
The researchers are now planning drug-drug interaction studies with substrates and inhibitors specific to P-gp.
CCA comprises a heterogeneous group of rare malignant tumors originating from biliary tree cells. Mortality is particularly high in intrahepatic CCA, a subtype of the disease, and has increased during the last few years. The effect of nonsurgical treatments on the disease is limited.
Reference
Yamamiya I, Hunt A, Takenaka T, et al. Evaluation of the cytochrome P450 3A and P-glycoprotein drug-drug interaction potential of futibatinib. Clin Pharmacol Drug Dev. Published online May 3, 2023. doi:10.1002/cpdd.1259
