Elunate Mechanism of Action

Pharmacology: Fruquintinib is a selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2 and 3, and has an inhibitory effect on VEGFR kinase activity, VEGFR 2/3 phosphorylation in cells and tissues, endothelial cell proliferation, and lumen formation, micro-angiogenesis in chick embryo chorioallantoic membrane model, and tumor angiogenesis, thereby inhibiting tumor growth.
Pharmacodynamics: Based on a concentration-QTc analysis in patients with colorectal cancer, fruquintinib had a relative low risk of causing heart rate-corrected QT interval prolongation (>10 ms) at the recommended dose (5mg once daily, 3 weeks on/1 week off), and no significant correlation was observed between fruquintinib plasma concentration and changes in QTc interval from baseline.
Clinical Trials: A randomised, controlled phase 3 FRESCO clinical study of fruquintinib monotherapy for metastatic colorectal cancer has been completed, and the main results are as follows.
Phase 3 clinical study (FRESCO): FRESCO is a randomised, double-blind, placebo-controlled, multicenter phase 3 clinical study comparing fruquintinib combined with BSC and placebo combined with BSC in patients with metastatic colorectal cancer who have failed the second-line or above standard chemotherapy. A total of 416 patients were randomised into the study based on a 2:1 ratio (278 patients in the fruquintinib arm, 138 patients in the placebo arm). Apart from one patient in the placebo arm who did not receive treatment, the other patients received either fruquintinib or placebo monotherapy, 5mg once daily via oral administration, with 3 weeks of continuous drug administration and 1 week of drug free period. The enrolled patients had histologically and/or cytologically confirmed metastatic colorectal cancer (stage IV), and had previously received at least second-line standard chemotherapy and failed (treatment failure was defined as occurrence of disease progression or intolerable toxicity during the treatment process or within 3 months after the last treatment; standard treatment regimens must include fluoropyrimidine, oxaliplatin and irinotecan). All patients had an Eastern Cooperative Oncology Group (ECOG) score of ≤1.
The median duration of treatment of the fruquintinib and placebo was 3.7 months and 1.8 months respectively. Refer to Table 1 for the main baseline status of patients. Except for the relatively high percentage of male patients (70.3%), the demographic and baseline characteristics in the placebo arm were basically consistent with those of the fruquintinib arm. (See Table 1.)

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The primary efficacy endpoint of the study was overall survival (OS), and the secondary efficacy endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and duration of response/duration of stable disease (DoR/ DoS). The OS of the fruquintinib arm was significantly prolonged, and the median OS was extended by 2.7 months and the risk of death was reduced by 35% as compared to the placebo arm. The secondary efficacy endpoints of fruquintinib were all significantly better than the placebo. Refer to Table 2 for the efficacy results. Refer to the figure as follows for the Kaplan-Meier curve of overall survival (OS). (See Table 2 and figure.)

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Pharmacokinetics: Absorption: In healthy subjects, the mean plasma maximum drug concentration (C_max) was 155 ng/mL, the median time to maximum drug concentration (T_max) was 3 hours (1.5 to 24 hours), and the mean area under the plasma drug concentration-time curve (AUC_0-∞) was 5,700 h·ng/mL following a single oral administration of 5mg fruquintinib capsules. In patients with advanced cancer, the mean C_max was 195 ng/mL, the median T_max was 2 hours (0.5 to 2 hours) and the mean AUC_0-72 was 5,495 h·ng/mL following a single oral administration of 5mg fruquintinib capsules.
The exposure (AUC) to fruquintinib within the dose range of 1mg to 6mg basically increased in proportion with the dose. The exposure to fruquintinib in patients with advanced cancer reached the steady state after 14 days of continuous once daily drug administration. The mean steady state exposure at 5mg (AUC_SS) was approximately thrice that of the first drug exposure (AUC_0-24).
Healthy subjects were given a single dose of 4mg of fruquintinib capsules via oral administration after a high-fat meal, and the C_max reduced by about 17% (the geometric mean ratio was 82.9%, and the 90% confidence interval was 76.7%-89.5%) and AUC_0-∞ was similar (the geometric mean ratio was 97.2%, and the 90% confidence interval was 94.0%-100.4%) as compared to the fasting state.
Distribution: The results of the in vitro study showed that the human plasma protein binding to fruquintinib was approximately 95.3%. After a single oral administration of 5mg of fruquintinib, the mean apparent volume of distribution at the elimination phase after oral administration was 32.5 L and 42.2 L in healthy subjects and patients with advanced cancer, respectively.
Metabolism: The in vivo metabolism and mass balance study of [¹⁴C] labeled fruquintinib showed that fruquintinib mainly exists in human plasma in its unchanged form, accounting for approximately 72% of total exposure in the plasma. The CYP3A4-mediated demethylated metabolites account for approximately 17% of total exposure in plasma. Other metabolic pathways include multiple site mono-oxidation, O-demethylation, N-demethylation, O-dequinazoline ring, and amide hydrolysis. The phase II metabolites are mainly glucuronide and sulphate conjugates of phase I products.
Excretion: In patients with advanced cancer who were orally administered with 2mg to 6mg of fruquintinib, the mean elimination half-life was 35.2 to 48.5 hours and the mean oral clearance was 9.98 to 17.8 mL/min. In healthy subjects who were orally administered with 5mg of ¹⁴C-labeled fruquintinib, the mean cumulative recovery of radioactive substances within 336 hours was 90.1%, including 60.3% in urine (0.5% was the unchanged drug) and 29.8% in stool (5.3% was the unchanged drug). Fruquintinib is mainly excreted as metabolites through the kidneys into urine.
Special Populations: Age, gender and body weight had no clinically significant effect on the pharmacokinetics of fruquintinib.
Patients with renal impairment: Based on the population pharmacokinetic analysis result, there were no significant clinical differences in the pharmacokinetics of fruquintinib between patients with mild renal impairment (creatinine clearance of 60 to 89 mL/min) and normal renal function. The pharmacokinetics of fruquintinib has not been evaluated in patients with moderate or severe renal impairment.
Drug Interactions: Effect of CYP3A inhibitors on fruquintinib: No significant changes in fruquintinib exposure (C_max and AUC) were observed when fruquintinib was in combination with multiple doses of itraconazole, a strong CYP3A inhibitor (200mg BID on the first day, followed by 200mg QD).
Effect of CYP3A inducers on fruquintinib: Coadministration of multiple doses of rifampicin (600mg QD), a strong CYP3A inducer, the C_max of fruquintinib was reduced by 12% and the AUC_0-∞ was reduced by 65%. Based on the physiological-based pharmacokinetic modeling (PBPK) and simulation results, there was no significant change in the C_max of fruquintinib and AUC_0-∞ was reduced by 28% when fruquintinib was in combination with multiple doses of efavirenz, a moderate CYP3A inducer (600mg QD); there was no significant change in C_max or AUC_0-∞ when fruquintinib was in combination with multiple doses of dexamethasone (8mg BID), a weak CYP3A inducer.
Effect of Gastric Acid Reducing Agents on fruquintinib: In the clinical pharmacokinetic study, no significant differences in fruquintinib exposure (C_max and AUC) were observed when coadministration of multiple doses of proton pump inhibitor (PPI) rabeprazole.
Effect of fruquintinib on transporter substrates: Fruquintinib has an inhibitory effect on efflux transporter P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) as shown by in vitro data.
Pharmacogenetics: Pharmacogenetic data is not available for this product.
Toxicology: Toxicological studies: General toxicity: In a 26-week oral gavage repeated-dose toxicity study in rats, the lowest-observed-adverse-effect level was 0.5/0.25mg/kg/day (the dose was decreased from Day 50 of dosing phase), and the target organs were bile duct, liver, kidneys, adrenal glands, thymus, spleen and femur. In a 39-week oral repeated-dose toxicity study in dogs, the no observed adverse effect level was 0.03mg/kg/day, and the main target organs were liver, kidneys, thymus, spleen, lymph nodes and gastrointestinal tract.
Genotoxicity: The Ames test and the mice bone marrow micronucleus test of fruquintinib were negative. The chromosome aberration test results of fruquintinib in Chinese hamster lung fibroblasts were positive under non-metabolic activation conditions for 24 hours (36μg/mL), and the results were negative under metabolic activation conditions (up to 36μg/mL).
Reproductive Toxicity: Oral administration of fruquintinib to male rats up to 3mg/kg/day and oral administration of fruquintinib to female rats up to 0.5mg/kg/day had no adverse effect on the fertility of male or female rats. At 0.5mg/kg/day, fruquintinib caused an increase in the number of absorbed embryos and number of post-implantation losses and a decrease in the number of live fetuses. The no-observed adverse effect level (NOAEL) on early embryonic development in rats was 0.15mg/kg/day, which was about 0.29 times the recommended clinical dose for humans (5mg/day) based on body surface area conversion.
Fruquintinib was orally administered to rats from gestation days (GDs) 6 to 15, the NOAEL was 0.025mg/kg/day for embryo-fetal development, which was about 0.048 times the recommended clinical dose for humans (5mg/day) based on the conversion of body surface area, and about 2.8% of the recommended clinical dose for humans (5mg/d) based on AUC. Fruquintinib caused decreased fetal weight, malformation and delayed ossification at doses of 0.1mg/kg/day and above. No significant accumulation of fruquintinib was observed in pregnant rats.
Carcinogenicity: No carcinogenicity study was conducted for fruquintinib.