A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib
Abstract 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 pharmaco...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-09-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13585 |
| _version_ | 1797687138863546368 |
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| author | Ling Gao Ikuo Yamamiya Mark Pinti Juan Carlos Rondon Thomas Marbury Gareth Tomlinson Lukas Makris Nanae Hangai Volker Wacheck |
| author_facet | Ling Gao Ikuo Yamamiya Mark Pinti Juan Carlos Rondon Thomas Marbury Gareth Tomlinson Lukas Makris Nanae Hangai Volker Wacheck |
| author_sort | Ling Gao |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-12T01:13:58Z |
| format | Article |
| id | doaj.art-b077c94b7d0f489a9fe5adf752ecaf3c |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-03-12T01:13:58Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-b077c94b7d0f489a9fe5adf752ecaf3c2023-09-13T21:15:53ZengWileyClinical and Translational Science1752-80541752-80622023-09-011691713172410.1111/cts.13585A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinibLing Gao0Ikuo Yamamiya1Mark Pinti2Juan Carlos Rondon3Thomas Marbury4Gareth Tomlinson5Lukas Makris6Nanae Hangai7Volker Wacheck8Taiho Oncology, Inc. Princeton New Jersey USATaiho Pharmaceutical Co., Ltd. Tsukuba JapanTaiho Oncology, Inc. Princeton New Jersey USAClinical Pharmacology of Miami Hialeah Florida USAOrlando Clinical Research Center Orlando Florida USATaiho Oncology, Inc. Princeton New Jersey USATaiho Oncology, Inc. Princeton New Jersey USATaiho Oncology, Inc. Princeton New Jersey USATaiho Oncology, Inc. Princeton New Jersey USAAbstract 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.https://doi.org/10.1111/cts.13585 |
| spellingShingle | Ling Gao Ikuo Yamamiya Mark Pinti Juan Carlos Rondon Thomas Marbury Gareth Tomlinson Lukas Makris Nanae Hangai Volker Wacheck A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib Clinical and Translational Science |
| title | A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib |
| title_full | A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib |
| title_fullStr | A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib |
| title_full_unstemmed | A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib |
| title_short | A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib |
| title_sort | phase i open label single dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib |
| url | https://doi.org/10.1111/cts.13585 |
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