025: No Clinically Meaningful Drug Interaction Between Futibatinib & Digoxin, Rosuvastatin or Quinidine

Statement of Purpose, Innovation or Hypothesis: Fibroblast growth factor receptor (FGFR) attenuation results in tumor growth inhibition and is an ideal target for oncologic treatment. Futibatinib is a novel oral, highly selective FGFR 1-4 tyrosine kinase inhibitor being developed to treat advanced cancers. Co-administration of futibatinib with itraconazole, a P-glycoprotein (P-gp) and strong cytochrome P450 3A (CYP3A) inhibitor, resulted in an increase of futibatinib exposure by ~50%. While these results indicate futibatinib is primarily metabolized by CYP3A, the extent to which P-gp inhibition contributed to the effect remains to be fully elucidated.In vitro studies suggest that futibatinib is a substrate and inhibitor of P-gp as well as a breast cancer resistant protein (BCRP) substrate. Therefore, a drug-drug interaction (DDI) study with P-gp and BCRP substrates and a P-gp inhibitor was performed to investigate the effect of futibatinib on these drug transporters.

Description of Methods & Materials: An open-label, fixed-sequence, 2-part, 2-period DDI study was conducted in 44 healthy volunteer participants to determine the effect of futibatinib on P-gp and BCRP substrates (digoxin + rosuvastatin cocktail; Part 1) and the effect of a P-gp inhibitor (quinidine; Part 2) on futibatinib, as outlined in Figure 1. Plasma and urine (digoxin only) pharmacokinetic (PK) parameters were assessed with standard equivalence statistical analyses.

Data & Results: In Part 1, futibatinib had minimal effects on the digoxin + rosuvastatin cocktail drug exposures. Plasma digoxin area-under the curve (AUC) and peak concentration (Cmax) revealed no change and ~5% increase with futibatinib co-administration, respectively. The 90% CIs around the GMRs for plasma and urine digoxin PK parameters were entirely contained within the conventional equivalence range of 80 - 125% indicating a lack of DDI effect. Similarly, rosuvastatin AUC (13%) and Cmax (~10%) minimally increased when co-administered with futibatinib. In Part 2, futibatinib AUC and Cmax exposures increased by 17% and 8% respectively, following quinidine co-administration, thus considered not to be a clinically relevant increase. There were no serious adverse events (AEs) in either study part. Futibatinib, when administered either alone or with digoxin + rosuvastatin or quinidine, was safe and well tolerated in healthy adult subjects. The most common AE was diarrhea, reported by 80% of participants in Part 1. Hyperphosphatemia, a known off-target AE of FGFR inhibitors, was experienced by 75% of subjects yet was reversible upon completion of futibatinib dosing. The majority of AEs in Part 2 were related to QTcF prolongation associated with quinidine administration alone.

Interpretation, Conclusion or Significance: Overall, futibatinib had no impact on plasma digoxin (a P-gp substrate) exposure and no clinically relevant effect on plasma rosuvastatin (a BCRP substrate) exposure, suggesting lack of clinically meaningful effects on these drug transporters. In addition, co-administration with quinidine (a P-gp inhibitor) revealed that the contribution of P-gp to futibatinib absorption appeared to be limited, and clinical perpetrators of P-gp are unlikely to have a clinically meaningful effect on the bioavailability of futibatinib. Altogether, these findings support the concomitant administration of futibatinib with other drugs that are P-gp and BCRP substrates and/or P-gp inhibitors.

Disclosures: This study was funded by Taiho Oncology, Inc.

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