Chemical formula: C₂₂H₂₂N₆O₃ Molecular mass: 418.448 g/mol PubChem compound: 71621331
Constitutive fibroblast growth factor receptor (FGFR) signalling can support the proliferation and survival of malignant cells. Futibatinib is a tyrosine kinase inhibitor that irreversibly inhibits FGFR 1, 2, 3, and 4 by covalent binding. Futibatinib exhibited in vitro inhibitory activity against FGFR2 resistance mutations (N550H, V565I, E566G, K660M).
Futibatinib increased serum phosphate level as a consequence of FGFR inhibition. Phosphate-lowering therapy and dose modifications are recommended to manage hyperphosphatemia.
The pharmacokinetics of futibatinib were evaluated in patients with advanced cancer administered 20 mg once daily unless otherwise specified.
Futibatinib exhibits linear pharmacokinetics over the dose range of 4 to 24 mg. Steady-state was reached after the first dose with a geometric mean accumulation ratio of 1.03. The geometric mean steady-state AUCss was 790 ng·h/mL (44.7% gCV) and Cmax,ss was 144 ng/mL (50.3% gCV) at the recommended dosage of 20 mg once daily.
Median time to achieve peak plasma concentration (tmax) was 2 (range: 1.2 to 22.8) hours.
No clinically meaningful differences in futibatinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (900 calories to 1000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects.
Futibatinib is approximately 95% bound to human plasma proteins, predominantly to albumin and α1-acid glycoprotein. The estimated apparent volume of distribution was 66.1 L (17.5%).
Futibatinib is predominantly metabolised by CYP3A (40-50%) as well as glutathione conjugation (50-60%) in vitro. Following oral administration of a single 20 mg radiolabelled futibatinib dose in healthy adult male subjects, the main drug-related moiety in plasma was unchanged futibatinib (59.19% of the total sample radioactivity) in a human [14C] mass balance study in healthy adult male subjects, followed by one inactive metabolite, a cysteinylglycine conjugate TAS-06-22952 (at >10% of dose).
The mean elimination half-life (t1/2) of futibatinib was 2.94 (26.5% CV) hours and the geometric mean apparent clearance (CL/F) was 19.8 L/h (23.0%).
Following a single oral dose of 20 mg radiolabelled futibatinib in healthy adult male subjects, approximately 64% of the dose was recovered in faeces and 6% in urine. Futibatinib excretion in unchanged form was negligible in either urine or faeces.
In vitro studies indicate that futibatinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, and does not induce CYP2B6 or CYP3A4 at clinically relevant concentrations.
In vitro studies indicated that futibatinib inhibited P-gp and BCRP, but didn’t inhibit OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1 or MATE2K at clinically relevant concentrations. Futibatinib is a substrate of P-gp and BCRP in vitro. Inhibition of BCRP is not expected to result in clinically relevant changes in the exposure of futibatinib.
No clinically meaningful differences in the systemic exposure (less than 25% difference in AUC) of futibatinib were observed based on age (18-82 years), sex, race/ethnicity, body weight (36-152 kg), mild to moderate renal impairment, or hepatic impairment. The effect of severe renal impairment and renal dialysis in end-stage renal disease on futibatinib exposure is unknown.
Compared to subjects with normal hepatic function, systemic exposure following a single dose of futibatinib was similar in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment.
Dose-dependent increase in blood phosphate levels was observed following once daily futibatinib 4 mg to 24 mg dose range.
No statistically significant exposure-efficacy relationships observed for ORR within the exposure range produced by futibatinib 20 mg once daily regimen.
The main toxicological findings following repeat-dose administration of futibatinib in both rats and dogs were related to the pharmacological activity of futibatinib as an irreversible inhibitor of FGFR, including increased inorganic phosphorus and calcium in plasma, ectopic mineralization in various organs and tissues, lesions in bone/cartilage at futibatinib exposures lower than the human exposure at the clinical dose of 20 mg. Corneal lesions were found only in rats. These effects were reversible with the exception of ectopic mineralization.
Futibatinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay. It was positive in the in vitro chromosome aberration test in cultured Chinese hamster lung cell (CHL/IU), but negative in the bone marrow micronucleus assay in rat and didn’t induce DNA damage in comet assay in rats. Thus, futibatinib is overall non-genotoxic.
Carcinogenicity studies with futibatinib have not been conducted.
Dedicated fertility studies with futibatinib have not been conducted. In repeat dose toxicity studies, oral administration of futibatinib did not result in any dose-related findings likely to result in impaired fertility in male or female reproductive organs.
Oral administration of futibatinib to pregnant rats during the period of organogenesis resulted in 100% post-implantation loss at 10 mg/kg per day (approximately 3.15 times the human exposure by AUC at the recommended clinical dose). At 0.5 mg/kg per day (approximately 0.15 times the human exposure by AUC at the recommended clinical dose), reduced mean foetal body weight, an increase in foetal skeletal and visceral malformations including major blood vessel variations were observed.
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