Lenvatinib metabolite

[1]. Lenvatinib: A Promising Molecular Targeted Agent for Multiple Cancers. Cancer Control. 2018 Jan-Dec;25(1):1073274818789361.

[2]. Lenvatinib versus Bay 43-9006 in first-line treatment of patients with unresectable hepatocellularcarcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173.

Lenvatinib is a small-molecule tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), platelet-derived growth factor receptor α (PDGFRα), stem cell factor receptor (KIT), and transfection rearrangement receptor (RET). These receptors are crucial for tumor angiogenesis, and lenvatinib inhibits tumor angiogenesis by suppressing the function of these receptors. Phase I clinical trials of lenvatinib were conducted simultaneously in Japan, Europe, and the United States, and tumor shrinkage effects were observed in thyroid cancer, endometrial cancer, melanoma, renal cell carcinoma, sarcoma, and colon cancer. Lenvatinib is a promising drug that has shown efficacy in treating a variety of solid tumors. Adverse reactions to lenvatinib treatment may include hypertension, proteinuria, diarrhea, and delayed wound healing. Managing these adverse events is also crucial for the use of lenvatinib. In this short review article, we summarize the current status, toxicities, and future prospects of lenvatinib in the treatment of thyroid cancer, hepatocellular carcinoma, renal cell carcinoma, and lung cancer. [1]

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Background: Lenvatinib (an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET, and KIT) showed activity against hepatocellular carcinoma in a phase II clinical trial. We aimed to compare lenvatinib with sorafenib as first-line treatment for patients with unresectable hepatocellular carcinoma. Methods: This was an open-label, phase III, multicenter, non-inferiority trial that enrolled patients with unresectable hepatocellular carcinoma who had not received prior treatment for advanced disease at 154 research centers in 20 countries across Asia Pacific, Europe, and North America. Patients were randomized 1:1 using an interactive voice response system, with grouping factors including: geographic location; gross portal vein invasion, extrahepatic metastasis, or both; Eastern Cooperative Oncology Group (ECOG) performance status score; and weight. Patients received either oral lenvatinib (12 mg daily for those weighing ≥60 kg, 8 mg daily for those weighing <60 kg) or sorafenib (400 mg twice daily) for 28 days as one course of treatment. The primary endpoint was overall survival, defined as the time from randomization to death from any cause. Efficacy analysis followed the intention-to-treat principle, and safety analysis included only patients who received treatment. The non-inferiority margin was set at 1.08. This trial was registered at ClinicalTrials.gov under registration number NCT01761266. Results: Between March 1, 2013, and July 30, 2015, a total of 1492 patients were enrolled. 954 eligible patients were randomized to either the lenvatinib group (n=478) or the sorafenib group (n=476). The median survival in the lenvatinib group was 13.6 months (95% CI 12.1–14.9), which was non-inferior to the sorafenib group (12.3 months, 10.4–13.9; hazard ratio 0.92, 95% CI 0.79–1.06), meeting the non-inferiority criteria. The most common adverse events of any grade in the lenvatinib group were hypertension (201 cases [42%]), diarrhea (184 cases [39%]), decreased appetite (162 cases [34%]), and weight loss (147 cases [31%]); the most common adverse events of any grade in the sorafenib group were hand-foot syndrome (249 cases [52%]), diarrhea (220 cases [46%]), hypertension (144 cases [30%]), and decreased appetite (127 cases [27%]). Conclusion: In treatment-naïve patients with advanced hepatocellular carcinoma, lenvatinib was non-inferior to sorafenib in terms of overall survival. The safety and tolerability of lenvatinib were consistent with previous observations. [2]

C20H17CLN4O4

412.83

412.093

417717-04-5

O-Demethyl Lenvatinib hydrochloride

135566046

Typically exists as solid at room temperature

1.6±0.0 g/cm3

644.1±0.0 °C at 760 mmHg

343.4±0.0 °C

0.0±0.0 mmHg at 25°C

1.739

4.23

4

5

5

29

619

0

O=C(C1C(O)=CC2N=CC=C(C=2C=1)OC1C=C(Cl)C(NC(NC2CC2)=O)=CC=1)N

XEZZOIWZFIDBIQ-UHFFFAOYSA-N

InChI=1S/C20H17ClN4O4/c21-14-7-11(3-4-15(14)25-20(28)24-10-1-2-10)29-18-5-6-23-16-9-17(26)13(19(22)27)8-12(16)18/h3-10,26H,1-2H2,(H2,22,27)(H2,24,25,28)

4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-hydroxyquinoline-6-carboxamide

417717-04-5; O-Demethyl Lenvatinib; Lenvatinib metabolite M2; 4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide; UNII-269N24780P; 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-hydroxyquinoline-6-carboxamide; 269N24780P; 6-Quinolinecarboxamide, 4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)