Chemical formula: C₂₁H₁₉N₃O₅ Molecular mass: 393.132 g/mol PubChem compound: 44480399
Fruquintinib is a selective tyrosine kinase inhibitor of VEGFR-1, -2, and -3 with antitumor effects resulting from suppression of tumour angiogenesis.
No prolongation of heart rate-corrected QT (QTc) interval (>10 milliseconds) was observed at the recommended dosage of fruquintinib. A concentration-QT analysis (N=205) showed no evidence of an association between fruquintinib plasma concentrations and changes in QTc interval from baseline.
After oral administration of fruquintinib, the median time to achieve peak plasma fruquintinib concentration (Tmax) was approximately 2 hours. Fruquintinib showed a second absorption peak approximately 24 hours after drug administration. Following repeat once-daily dosing, fruquintinib exposure (Cmax and AUC0-24h) increased in a dose-proportional manner across the dose range of 1 to 6 mg (0.2 to 1.2 times the recommended dosage). Following administration of fruquintinib 5 mg once daily for 21 days with 7 days off of each 28-day cycle in patients with advanced solid tumours, steady state of fruquintinib was achieved after 14 days, and the mean accumulation based on AUC0-24h was 4-fold relative to a single dose. At the recommended dose of 5 mg of fruquintinib, the geometric mean (CV) Cmax and AUC0-24h for fruquintinib at steady state were 300 ng/mL (28) and 5880 ng*h/mL (29%), respectively.
Compared to the fasting state, a high-fat meal had no clinically meaningful effect on fruquintinib pharmacokinetics in healthy subjects. Fruquintinib can be administered with or without food.
The apparent volume of distribution of fruquintinib is approximately 48.5 L. Plasma protein binding of fruquintinib is approximately 95% in vitro and mainly bound to human serum albumin.
Fruquintinib is metabolised by multiple enzymes, including CYP450 (CYP3A and CYP2C subfamilies) and non-CYP450 enzyme systems. The in vivo metabolism and mass balance study of [14C] labelled fruquintinib showed that fruquintinib mainly exists in human plasma in its unchanged form, accounting for approximately 72% of total exposure in the plasma, and the CYP3A4-mediated N-demethyl metabolite of fruquintinib account for approximately 17% of total exposure in plasma. Other metabolic pathways include multi-site mono-oxidation, O-demethylation, N-demethylation, O-dequinazoline ring, and amide hydrolysis. The phase II metabolites are mainly glucuronic acid and sulphuric acid conjugates of phase I products.
Cytochrome P450 enzymes:
CYP3A4 was the main enzyme among the CYP isoforms involved in the metabolism of fruquintinib, with minor contributions from CYP2C8, CYP2C9 and CYP2C19. Fruquintinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A, or an inducer of CYP1A2, CYP2B6, CYP3A at therapeutically relevant concentrations.
Transporter systems:
Fruquintinib is not a substrate of P-glycoprotein (P-gp), organic anion transport protein (OATP)1B1, or OATP1B3. Fruquintinib inhibited P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in a dose-dependent manner in vitro and demonstrated pH-dependent aqueous solubility. Fruquintinib is not an inhibitor of OATP1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion protein (MATE)1, or MATE2-K at therapeutically relevant concentrations.
The apparent clearance (CL/F) of fruquintinib is 14.8 mL/min at steady-state after once daily dosing in patients with advanced solid tumours. The mean elimination half-life of fruquintinib is approximately 42 hours.
Following administration of a single 5 mg radiolabelled fruquintinib in healthy subjects, approximately 60% of the dose was recovered in urine (0.5% of the dose as unchanged fruquintinib), and 30% of the dose was recovered in faeces (5% of the dose as unchanged fruquintinib).
Based on the population pharmacokinetic analyses, mild to moderate renal impairment (creatinine clearance [CrCL] 30 to 89 mL/min) had no clinically meaningful impact on fruquintinib pharmacokinetics. In a pharmacokinetic study, unbound fruquintinib AUC0-inf and Cmax were similar in subjects with moderate (CrCL 30–59 mL/min, N=8) or severe (CrCL 15–29 mL/min, N=8) renal impairment as compared to subjects with normal renal function (CrCL ≥90 mL/min, N=8).
No clinically meaningful differences in the pharmacokinetics of fruquintinib were observed between patients with normal hepatic function and patients with mild (total bilirubin ≤ ULN with AST greater than ULN or total bilirubin >1 to 1.5 times ULN with any AST) hepatic impairment based on population pharmacokinetic analyses. Based on a dedicated hepatic impairment pharmacokinetic study, following administration of a single 2 mg oral dose of fruquintinib, no clinically meaningful differences in the dose-normalised AUC of fruquintinib were observed in subjects with moderate (Child Pugh B) hepatic impairment compared to subjects with normal hepatic function.
Population pharmacokinetic analyses showed that age (18 to 82 years), body weight (48 to 108 kg), gender or race had no clinically relevant impact on the pharmacokinetics of fruquintinib.
No pharmacokinetic studies were performed with fruquintinib in patients under 18 years of age.
In repeat dose and reproductive toxicity studies, toxicity was observed at fruquintinib average plasma concentrations below the expected human therapeutic concentrations.
In repeat dose animal toxicity studies, the main target organ effects were identified in the gastrointestinal tract, hepatobiliary system, immune system, skeletal system (femur and teeth), kidneys, hematopoietic system, and adrenal gland and appear related to the pharmacology of VEGFR inhibition and/or disruption of VEGF signalling pathway. All findings were reversible after 4 weeks without treatment, apart from the skeletal system (broken/lost teeth).
In a fertility and early embryonic development study in rats, male and female reproductive indices were decreased at exposures approximately 3.2 and 0.8-fold the human AUC, respectively. Dose-dependent increases in pre-implantation loss were observed in the same study.
In an embryo-foetal developmental study in rats, embryotoxic and teratogenic effects were observed at subclinical exposure levels in the absence of excessive maternal toxicity, consisting of foetal external, visceral, and skeletal malformations. Malformations affected primarily the head, tail, tongue, blood vessels, heart, thymus, and developing skeleton (notably vertebrae).
No evidence of genotoxicity was observed in in vitro and in vivo studies.
Carcinogenicity studies have not been performed with fruquintinib.
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