Apatinib Mesylate
Apatinib Mesylate was approved by China Food and Drug Administration (CFDA) on October 17, 2014. It was first synthesized by Advenchen Laboratories (USA), then developed and Marketed as 艾坦® by Jiangsu Hengrui Medicine.
Apatinib mesylate is an oral tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor 2. It is indicated for treatment of metastatic gastric carcinoma.
艾坦® is available as tablets for oral use, containing 250 mg, 375 mg or 425 mg of free Apatinib, and the recommended dose is 850 mg once daily.
Update Date：2016-03-14
- Drug Name：
- Apatinib Mesylate
- Research Code：
- YN-968D1
- Trade Name：
- 艾坦®
- MOA：
- VEGFR2 tyrosine kinase inhibitor
- Indication：
- Metastatic gastric carcinoma
- Status：
- Approved
- Company：
- HengRui (Originator)
- Sales：
- ATC Code：
Update Date：2015-07-29
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2014-10-17 | Marketing approval | 艾坦 | Metastatic gastric carcinoma | Tablet | 0.25 g/0.375 g/0.425 g | HengRui |
Update Date：2015-08-27
|
Molecular Weight | 493.58 | ||||||||||||
| Formula | C25H27N5O4S | |||||||||||||
| CAS No. |
811803-05-1 (Apatinib); 1218779-75-9 (Apatinib Mesylate); |
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| Chemical Name | N-[4-(cyanocyclopentyl)-phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide | |||||||||||||
| Apatinib （Free Acid/Base）Parameters： | ||||||||||||||
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| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-08-31
Update Date：2016-05-11
Update Date：2016-06-14
Mechanism of Action
Apatinib is an oral tyrosine kinase inhibitor targeting VEGFR-2 (IC50 = 1 nM), thereby inhibiting angiogenesis, which plays an important role in the growth and metastasis of malignant tumors.
Apatinib inhibited VEGFR-2, resulting in inhibition of angiogenesis, migration, and stimulated cell proliferation in vitro studies.
M1-1, a metabolite of apatinib, showed significant inhibition to VEGFR-2 (IC50 = 19.2 nM), c-kit (IC50 = 125 nM) and PDGFR-β (IC50 = 46.9 nM).
Apatinib inhibited the growth in a broad range of xenografted human tumors in vivo in a dose-dependent manner, but did not inhibit the growth of these cancer cell lines in vitro, suggesting that the antitumor activity was via an anti-angiogenic mechanism rather than due to a direct inhibition of cell proliferation.
In Vitro Efficacy
Apatinib inhibited phosphorylation of RTKs and its related downstream molecules in cells:
● VEGFR and ERK1/2: Completely blocked at 10 µM.
● c-kit and PDGFR: Completely blocked at 1 µM.
● HER2 and EGFR: No effect.
Inhibited proliferation of HUVEC cells:
● In 20% FBS condition: IC50 = 23.4 nM.
● Activated by VEGF: IC50 = 0.17 nM.
Inhibited in vitro angiogenesis and migration:
● In HUVEC tube formation assay: Significant inhibition at 1 µM.
● In HUVEC transwell migration assay: Significant inhibition at 1 µM.
● In microvessel growth from rat aortic ring: Significant inhibition at 0.1 µM.
In Vivo Efficacy
Tumor growth inhibition in human lung carcinoma xenograft mice models:
● Significant inhibition at 100 mg/kg/day in both NCI-H460 (T/C% = 57%) and A549 (T/C% = 41%) models.
● Apatinib was enhanced by the combination with docetaxel or doxorubicin (P <0.05) in NCI-H460 model.
Tumor growth inhibition in human colon carcinoma xenograft mice models:
● Significant inhibition at 50 mg/kg/day in both HCT-116 (T/C% = 63%), HT-29 (T/C% = 59%), and Ls174t (T/C% = 72%) models.
● Apatinib was enhanced by the combination with oxaliplatin or 5-FU (P <0.05) in Ls174t model.
Tumor growth inhibition in human stomach carcinoma SGC-7901 xenograft mice models:
● Significant at 100 mg/kg/day (T/C% = 33%).
Update Date：2016-06-14
Absorption of Apatinib
Had low oral bioavailability in male dogs (9.24%) and female dogs (15.4%) after single oral administration of apatinib mesylate. [7]
Was absorbed moderately in humans (Tmax = 2.9 h) and in rats (1.33 h).
Showed a half-life ranging between 8-9 h in humans after oral administration, longer than that in rats (1.78 h).
Distribution of Apatinib
Apatinib and M1-1 exhibited high plasma protein binding in humans (92.4% and 90.1%), M1-2 and M1-6 exhibited moderate plasma protein binding (88% and 75.8%).
Metabolism of Apatinib
Was extensively metabolized in human liver microsomes and recombinant enzymes.
Was metabolized primarily by CYP3A4/5, to a lesser extent, by CYP2D6, 2C9 and 2E1.
UGT2B7 was the main enzyme responsible for the formation of M9-2. Both UGT1A4 and UGT2B7 were responsible for the formation of Z-3-hydroxy-apatinib-O-glucuronide (M9-1). [7]
Overall, the parent drug represented the most abundant component in human plasma, with M9-2 (O-glucuronide) as the major metabolite.
The steady-state exposures of E-3-hydroxy-apatinib (M1-1), Z-3-hydroxy-apatinib (M1-2), and apatinib-25-N-oxide (M1-6) were 56%, 22% and 32% of parent drug exposure, respectively. [7]
M1-1, M1-2 and M1-6 were pharmacologically active in inhibiting VEGFR-2 and VEGFR-β, but the major circulating metabolite (M9-2) was inactive
Excretion of Apatinib
Was predominantly excreted in feces with the parent drug as the most significant component in human feces.
Unchanged apatinib was detected in negligible quantities in urine, indicating that systemically available apatinib was extensively metabolized.
Drug-Drug Interaction [11]
Apatinib had a higher affinity for BCRP compared with P-gp and it was likely a substrate for both BCRP and P-gp.
Apatinib significantly inhibited P-gp (IC50 = 2.9 μM) and BCRP-mediated (IC50 = 11 μM) transport in MDR cells.
Apatinib did not significantly alter the mRNA or protein levels of P-gp and BCRP.
Update Date：2016-06-14
Single-Dose Toxicity
Dog MTD: 30 mg/kg. [9]
Repeated-Dose Toxicity
Not available.
Safety Pharmacology
Not available.
Genotoxicity
Not available.
Repeated-Dose Toxicity
Not available.
Carcinogenicity
Not available.