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AZD6244 (Selumetinib), a MEK inhibitor

time:2017-05-04 17:25:46 source:

ARRY-142886 (Selumetinib, AZD6244) is a small molecule MEK inhibitor developed by Array BioPharma in america. MEK1 IC50 14 nmol/L, molecular weight 458. AZD6244 (Selumetinib), a MEK inhibitor [1] the influence of food: food will delay the absorption of Selumetinib, about 2.5 hours, should be taken on an empty stomach. Reference: A phase I, open-label randomized, crossover study to assess the effect of dosing of the MEK 1/2 inhibitor Selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors [2] form: hydrogen sulfate, hydrogen, sulfate, salt (AZD6244, Hyd-Sulfate), pKa:2.7, 8.2. The bioavailability of AZD6244 salts is 2.5 times that of free bases. Reference: The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Banerji, U, Camidge, DR, Verheul, HM, Agarwal, R, Sarker, SB, Desar, IM, Timmer-Bonte, JN, Eckhardt, SG, Lewis, KD, Brown, KH, Cantarini, MV, Morris, C, D,, George, SM, Kaye, CM, Smith, PD, van, Herpen Clin Cancer Res. 2010 Mar 1; 16 (5): 1613-23. [3] dosage: minimum dose 100mg per day, two times a day, once 50mg; maximum dose (MTD) 150mg per day, two times a day, once 75mg. Iressa / Tarceva plus selumetinib, morning / special one night, selumetinib a grain of 100mg. [4] pharmacokinetics: hepatic P450 (CYPs), 1A2, 2C19, and, 3A4 metabolism. The highest blood concentration was reached 1.5 hours after oral administration, with a half-life of about 5-8 hours. [5] Clinical trials: (1) Phase, I, pharmacokinetic, and, pharmacodynamic, study, the, oral, small-molecule, mitogen-activated, protein, kinase, kinase, 1/2, inhibitor, AZD6244 (ARRY-142886), in,, patients, with, advanced, of, cancers. Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade The PKs were 1 or 2. less than dose proportional with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated >or= 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in assessable tumor samples. 10 of 26 Nine patients had stable disease (SD for >or= 5 Mon) Ths, including, two, patients, with, for, SD 19 (thyroid, cancer), and 22 (uveal, melanoma, plus, renal, cancer) 28-day cycles. (2) A phase II, open-label randomized, study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. INTRODUCTION: AZD6244 (ARRY-142886) is a potent, selective MEK inhibitor. This study aimed to evaluate the efficacy and safety of AZD6244 versus pemetrexed as second- or third-line treatment in patients with advanced non-small cell lung cancer (NSCLC). METHODS: In this randomized phase II study patients received either mg oral AZD6244 free-base suspension twice 100 daily or 500 mg/m (2) intravenous pemetrexed once every after pretreatment with a 3 weeks corticosteroid, folic acid, and vitamin B12. The primary end point of the study was the disease progression event count. RESULTS: Eighty-four patients were randomized. Disease progression events were experienced by 28 (and 70%) 26 (59%) patients in the AZD6244 and pemetrexed groups, respectively. Median progression-free survival was not statistically significantly different between the AZD6244 and pemetrexed groups (67 versus 90 days, respectively; hazard ratio 1.08, two-sided 80% confidence, interval = 0.75-1.54; P = 0.79). Two patients in the AZD6244 group had a best response to treatment of partial response. In the pemetrexed group, one patient achieved a complete response and one patient a partial response. Dermatitis acneiform, diarrhea, nausea, and vomiting were the most frequently reported adverse events with AZD6244, compared with fatigue, anemia, NAU Sea, anorexia, and, dermatitis, acneiform, with, pemetrexed. CONCLUSIONS: Oral AZD6244 showed clinical activity as second- or third-line therapy for patients with advanced NSCLC. In an unselected NSCLC population, there is no suggestion that AZD6244 monotherapy offers any advantage over standard treatment with pemetrexed. Based on preclinical data and recent clinical observations, further development of AZD6244 in NSCLC should focus on BRAF or RAS mutation-positive patients and/or AZD6244-based combination regimens. (3) Phase, II, double-blind, randomized, placebo-controlled, multi-center, trial; NCT00890825 In June 4, 2012, a two phase of a randomized double-blind trial was published at the annual meeting of the American Society for clinical oncology in Chicago. The research was carried out by AstraZeneca and applied jointly with selumetinib (AZD6244/ARRY-886)

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