Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies

Department of Medical Oncology, Fudan University Shanghai Cancer Center, PR China.
BMC Cancer (Impact Factor: 3.36). 10/2010; 10(1):529. DOI: 10.1186/1471-2407-10-529
Source: PubMed


YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies.
This dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death.
Forty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks.
The recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations. unique identifier: NCT00633490.

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Available from: Ke Yu, Jul 15, 2015
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    • "Apatinib, also known as YN968D1, is a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2 (VEGFR2, also known as KDR). It is an orally bioavailable, small molecule agent which is thought to inhibit angiogenesis in cancer cells; specifically apatinib inhibits VEGF-mediated endothelial cell migration and proliferation, thus blocking new blood vessel formation in tumor tissue [6]. "
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    ABSTRACT: Elemene, a compound found in an herb used in traditional Chinese medicine, has shown promising anticancer effects against a broad spectrum of tumors. In an in vivo experiment, we found that apatinib, a tyrosine kinase inhibitor that selectively inhibits VEGFR2, combined with elemene injection (Ele) for the treatment of H22 solid tumor in mice resulted in worse effectiveness than apatinib alone. Moreover, Ele could protect HepG2 cells from death induced by serum-free starvation. Further data on the mechanism study revealed that Ele induced protective autophagy and prevented human hepatoma cancer cells from undergoing apoptosis. Proapoptosis effect of Ele was enhanced when proautophagy effect was inhibited by hydroxychloroquine. Above all, Ele has the effect of protecting cancer cells from death either in apatinib induced nutrient deficient environment or in serum-free induced starvation. A combination of elemene injection with autophagy inhibitor might thus be a useful therapeutic option for hepatocellular carcinoma.
    Evidence-based Complementary and Alternative Medicine 07/2014; 2014:637528. DOI:10.1155/2014/637528 · 1.88 Impact Factor
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    • "The increased understanding of the role of signaling pathways in promoting tumor angiogenesis has led to the rational development of new targeted therapeutic agents. Since aberrantly activated vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) signaling pathways are associated with enhanced angiogenesis in tumors [3] [4], inhibition of VEGFR and PDGFR signalings has been proposed as an effective therapeutic approach to solid malignancies. For example, sunitinib, a small molecular synthetic drug targeting multiple tyrosine kinase receptors, was the first ever oncology product approved by USA Food and Drug Administration for two indications, renal cell carcinoma and gastrointestinal stromal tumor, simultaneously [5]. "
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    ABSTRACT: Henatinib is a novel oral small-molecule multikinase inhibitor that has demonstrated broad and potent antitumor activities in preclinical studies. In support of a clinical pharmacokinetic study, a simple, sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of henatinib in human plasma and urine. The sample preparation procedure involved a simple protein precipitation with methanol and the addition of midazolam as the internal standard. The chromatographic separation was achieved on an XBridge C18 column (50mm×2.1mm, 2.5μm) using a mixture of 5mM ammonium formate (pH 9.5)-acetonitrile-methanol (60:30:10, v/v/v) as the mobile phase. The MS/MS detection was performed in the positive ion multiple reaction monitoring (MRM) mode by monitoring the precursor→product ion transitions at m/z 469.1→382.2 for henatinib and m/z 326.2→291.3 for the internal standard. Assays were validated over the concentration range of 0.100-400ng/mL and 1.00-2500ng/mL for plasma and urine, respectively. The established method was highly sensitive with the lower limit of quantification (LLOQ) of 0.100ng/mL and 1.00ng/mL for plasma and urine, respectively. The intra- and inter-day precisions were <8.6% and <9.2% for plasma and urine, respectively. The mean assay accuracy was within ±6.8% of nominal values for both plasma and urine. The analytical runtime within 3.5min per sample made this method suitable for high-throughput determination. The validated method was successfully applied to a phase I dose escalation pharmacokinetic study in Chinese cancer patients.
    Journal of pharmaceutical and biomedical analysis 03/2013; 80C:173-179. DOI:10.1016/j.jpba.2013.03.010 · 2.98 Impact Factor
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    • "The results from a phase 1 clinical study conducted in patients with advanced solid tumors have shown that apatinib can be well tolerated and exhibits substantial antitumor activity across a broad range of malignancies at the recommended dose of 750 mg once daily (Li et al., 2010). The pharmacokinetic parameters of apatinib in plasma were also calculated using noncompartmental analysis. "
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    ABSTRACT: Apatinib is a new oral anti-angiogenic molecule that inhibits VEGFR-2. The present study aims to determine the metabolism, pharmacokinetics, and excretion of apatinib in humans and to identify the enzymes responsible for its metabolism. The primary routes of apatinib biotransformation included cis- and trans-cyclopentyl-3-hydroxylation, N-dealkylation, pyridyl-25-N-oxidation, 16-hydroxylation, dioxygenation, and O-glucuronidation after 3-hydroxylation. Nine major metabolites were confirmed by comparison with reference standards. The total recovery of the administered dose was 76.8% within 96 h post-dose, with 69.8% and 7.02% of the administered dose excreted in feces and urine, respectively. About 59.0% of the administered dose was excreted unchanged via feces. Unchanged apatinib was detected in negligible quantities in urine, indicating the systemically available apatinib was extensively metabolized. The major circulating metabolite was the pharmacologically inactive cis-3-hydroxy-apatinib-O-glucuronide (M9-2), the steady state exposure of which was 125% that of the apatinib. The steady state exposures of cis-3-hydroxy-apatinib (M1-1), trans-3-hydroxy-apatinib (M1-2), and apatinib-25-N-oxide (M1-6) were 56%, 22%, and 32% of parent drug exposure, respectively. Calculated as pharmacological activity index values, the contribution of M1-1 to the pharmacology of the drug was 5.42% to 19.3% that of the parent drug. The contribution of M1-2 and M1-6 to the pharmacology of the drug was less than 1%. Therefore, apatinib was a major contributor to the overall pharmacological activity in humans. Apatinib was primarily metabolized by CYP3A4/5 and, to a lesser extent, by CYP2D6, CYP2C9, and CYP2E1. UGT2B7 was the main enzyme responsible for M9-2 formation. Both UGT1A4 and UGT2B7 were responsible for trans-3-hydroxy-apatinib-O-glucuronide (M9-1) formation.
    Drug metabolism and disposition: the biological fate of chemicals 03/2013; 41(6). DOI:10.1124/dmd.112.050310 · 3.25 Impact Factor
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