Evaluation of the Mass Balance and Metabolic Profile of Futibatinib in Healthy Participants

Yamamiya, Ikuo; Hunt, Allen; Yamashita, Fumiya; Sonnichsen, Daryl; Muto, Toshiharu; He, Yaohua; Benhadji, Karim A.

doi:10.1002/cpdd.1271

Cited by 4 publications

(1 citation statement)

References 26 publications

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“…In a phase I mass balance study in healthy male adults, the total amount of unchanged futibatinib in urine and feces was negligible, indicating that metabolism is the predominant elimination pathway for futibatinib. 16 More than 90% of radioactivity was recovered in feces, demonstrating that the renal route plays a minimal role in futibatinib elimination. Despite an in vitro study suggesting that cytochrome P450 (CYP450)–related metabolism contributed to ~50% of the overall metabolism, the major metabolite (>10% of total exposure of futibatinib‐related compounds) was a derivative of glutathione conjugate.…”

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confidence: 99%

A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib

Gao

Yamamiya

Pinti

et al. 2023

Clinical Translational Sci

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Futibatinib is a covalently binding FGFR1–4 inhibitor that received US Food and Drug Administration approval for the treatment of patients with previously treated, advanced intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions/rearrangements. This phase I trial evaluated the pharmacokinetics (PKs), safety, and tolerability of futibatinib in subjects with impaired hepatic function and matched healthy volunteers. Twenty‐two subjects with hepatic impairment (8 mild [Child‐Pugh 5–6], 8 moderate [7–9], and 6 severe [10–15]) and 16 matched healthy control subjects received a single oral dose of futibatinib 20 mg. Futibatinib PKs were compared between subjects with mild/moderate/severe hepatic impairment and each corresponding control cohort and the overall control cohort. Relationships between futibatinib PKs and Child‐Pugh scores and liver function tests were examined via scatter/regression plots. Compared with matched controls, the area under the plasma concentration–time curve from time zero to infinity increased by 21%/20%/18% and the maximum plasma concentration (Cmax) increased by 43%/15%/10% in subjects with mild/moderate/severe hepatic impairment, respectively. Changes were not considered clinically relevant: geometric mean ratios were within 80%–125%, except for Cmax in subjects with mild hepatic impairment (143%). No obvious trends were observed among futibatinib PK parameters versus Child‐Pugh scores, bilirubin, albumin, international normalized ratio, and aspartate aminotransferase (all p > 0.05). Futibatinib was well‐tolerated, with only four grade 1 treatment‐emergent adverse events (mild hepatic impairment = 2 and control = 2). The results demonstrate that futibatinib dose adjustments due to mild/moderate/severe hepatic impairment are not necessary in patients receiving futibatinib 20 mg daily.

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Section: Introductionmentioning

confidence: 99%

A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib

Gao

Yamamiya

Pinti

et al. 2023

Clinical Translational Sci

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

Yamamiya

Hunt

Takenaka

et al. 2023

Clinical Pharm in Drug Dev

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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.

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The role of the methoxy group in approved drugs

Chiodi,

Ishihara

2024

European Journal of Medicinal Chemistry

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Evaluation of the Mass Balance and Metabolic Profile of Futibatinib in Healthy Participants

Cited by 4 publications

References 26 publications

A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib

A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib

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

The role of the methoxy group in approved drugs

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