Fruquintinib is primarily eliminated by CYP450 and non-CYP450 (i.e., sulfation and glucuronidation) metabolism. CYP3A and to a lesser extent CYP2C8, CYP2C9, and CYP2C19 are the CYP450 enzymes involved in fruquintinib metabolism.[9]
The potency of M11 for inhibiting VEGFR-2 kinase activity is 10 times lower than that of fruquintinib (Takeda data on file); therefore, M11 is not considered an active metabolite.
A previous study reported that following administration of 5 mg of radiolabeled fruquintinib, approximately 60% of the dose was recovered in urine (0.50% unchanged) and 30% was recovered in feces (5.34% unchanged), with the remaining radioactivity excreted as metabolites.
solubility of fruquintinib is pH-dependent, with a solubility of 0.9 μg/mL at pH 6.8 that increases underacidic conditions to 129.9 μg/mL at pH 1.
Fruquintinib is soluble in organic solvents suchas DMSO and dimethyl formamide (DMF). The solubility of fruquintinib in these solvents is approximately
Fruquintinib isindicated for adults with metastatic colorectal cancer who received priorfluoropyrimidine-,oxaliplatin-, andirinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.[6][11][13][14]
The earlier generation small molecule VEGFR inhibitors, such as sunitinib,22 sorafenib,23 regorafenib24 and pazopanib25 suffer frompoor kinome selectivity. In fact, many of them inhibit more than 10 kinases at similar potency.[15]
Fruquintinib is a highly potent andselective VEGFR 1, 2, 3 inhibitor
Fruquintinib was found to inhibit VEGFR2 (KDR) with an IC50 of 25 nmol/L in the Z-lyte assay. The kinase selectivity of fruquintinib was evaluated against a panel of 253 kinases using [32p-ATP] incorporation assay by Upstate Biotechnology Inc. (UBI) (Fig. 1B). The results showed that fruquintinib inhibited VEGFR family member (VEGFR1, 2, 3) withIC50s of 33 nmol/L, 35 nmol/L and 0.5 nmol/L, respectively with weak inhibition of RET, FGFR-1 and c-kit kinases. No significant inhibition was found against all other kinases at 1 μmol/L
Efficacy was evaluated in FRESCO-2 (NCT04322539) and FRESCO (NCT02314819).[11] FRESCO-2 (NCT04322539), an international, multicenter, randomized, double-blind, placebo-controlled trial, evaluated 691 participants with metastatic colorectal cancer who had disease progression during or after prior fluoropyrimidine-, oxaliplatin-, irinotecan-based chemotherapy, an anti-VEGF biological therapy an anti-EGFR biological therapy if RAS wild type, and at least one of trifluridine/tipiracil or regorafenib.[11] FRESCO, a multicenter, placebo-controlled trial conducted in China, evaluated 416 participants with metastatic colorectal cancer who had disease progression during or after prior fluoropyrimidine-, oxaliplatin, and irinotecan-based chemotherapy.[11]
In April 2024, theCommittee for Medicinal Products for Human Use (CHMP) of theEuropean Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Fruzaqla, intended for the treatment of people with previously treated metastatic colorectal cancer (mCRC).[7][16] The applicant for this medicinal product is Takeda Pharmaceuticals International AG Ireland Branch.[7] Fruzaqla was approved for medical use in the United States in June 2024.[8]
^abc"Fruzaqla EPAR".European Medicines Agency. 25 April 2024. Retrieved27 April 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ab"Fruzaqla PI".Union Register of medicinal products. 25 June 2024. Retrieved26 June 2024.
Clinical trial numberNCT04322539 for "A Study of Efficacy and Safety of Fruquintinib (HMPL-013) in Participants With Metastatic Colorectal Cancer (FRESCO-2)" atClinicalTrials.gov
Clinical trial numberNCT02314819 for "A Phase III Trial Evaluating Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer participants （FRESCO) (FRESCO)" atClinicalTrials.gov
This article incorporates text from this source, which is in thepublic domain.