Trametinib

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H317：Kann allergische Hautreaktionen verursachen.

  H361：Kann vermutlich die Fruchtbarkeit beeinträchtigen oder das Kind im Mutterleib schädigen.

  H372：Schädigt bei Hautkontakt und Verschlucken die Organe bei längerer oder wiederholter Exposition.

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

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  P260：Dampf/Aerosol/Nebel nicht einatmen.

  P261：Einatmen von Staub vermeiden.

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P270：Bei Gebrauch nicht essen, trinken oder rauchen.

  P272：Kontaminierte Arbeitskleidung nicht außerhalb des Arbeitsplatzes tragen.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P281：Vorgeschriebene persönliche Schutzausrüstung verwenden.

  P302+P352：BEI BERÜHRUNG MIT DER HAUT: Mit viel Wasser/... (Hersteller kann, falls zweckmäßig, ein Reinigungsmittel angeben oder, wenn Wasser eindeutig ungeeignet ist, ein alternatives Mittel empfehlen) waschen.

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  P314：Bei Unwohlsein ärztlichen Rat einholen / ärztliche Hilfe hinzuziehen.

  P321：Besondere Behandlung

  P333+P313：Bei Hautreizung oder -ausschlag: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

  P363：Kontaminierte Kleidung vor erneutem Tragen waschen.

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Trametinib Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Trametinib is an inhibitor of MEK1 and -2. It inhibits B-RAF- and C-RAF-induced phosphorylation of MEK1 (IC₅₀s = 3.4 and 1.8 nM, respectively) and MEK2 (IC₅₀s = 1.6 and 0.92 nM, respectively). Trametinib inhibits the growth of two human colorectal cancer cell lines expressing mutant B-RAF (IC₅₀s = 0.48 and 0.52 nM) and seven cell lines expressing mutant K-Ras (IC₅₀s = 2.2-174 nM) but does not inhibit the growth of wild-type COLO 320DM cells expressing both B-RAF and K-Ras (IC₅₀ = >10,000 nM). It reduces tumor growth in HT-29 and COLO 205 mouse xenograft models when used at doses of 0.3 and 1 mg/kg per day. Trametinib (0.03 and 0.1 mg/kg per day) also decreases M. tuberculosis-induced increases in hind paw volume in a rat model of arthritis. Formulations containing trametinib, in combination with dabrafenib, have been used in the treatment of metastatic mutant B-RAF^V600E melanoma.

• Verwenden

  Used in the systematic treatment of advanced cutaneous melanoma. An EGFR kinase inhibitor and potent MEK inhibitor.

• Verwenden

  antiprotozoal

• Verwenden

  Used in the systematic treatment of advanced cutaneous melanoma. An EGFR kinase inhibitor.

• Indications

  MEK, also known as MAPK, is a dual specificity threonine/tyrosine kinase that is a key node in the Raf–Ras–MEK signaling pathway. Small-molecule MEK inhibitors represent the largest group of type III allosteric inhibitors that do not bind to the ATP binding pocket. As of December 2016, besides the FDA-approved MEK1/2 inhibitors trametinib (Mekinist(R), GlaxoSmithKline) and cobimetinib (Cotellic(R), Roche), over 10 MEK inhibitors are currently in clinical trials. Trametinib was approved by FDA in 2013 for the treatment of patients with either B-Raf V600E or V600K mutated metastatic melanoma. Considering the fact that MEK and Raf are different kinases along the same pathway of Ras–Raf–MEK/ERK signaling cascade, combination strategies using both MEK and B-Raf inhibitors were utilized to overcome the observed progression using single-agent trametinib, which usually occurs within 7months. FDA approved the combination of trametinib and dabrafenib for the treatment of B-Raf V600E/K mutated metastatic melanoma in January 2014 and the combination of cobimetinib and vemurafenib for the same type of indication. Although significant improvement in progression-free survival was observed using MEK/B-Raf combination strategy, the incidence of some common adverse effects, such as vomiting, diarrhea, nausea, rash, and pyrexia, also increased.

• Definition

  ChEBI: A pyridopyrimidine that is used (as its dimethyl sulfoxide addition compound) for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, and who have not received prior BRAF inhibitor treatment.

• Trademarks

  Mekinist

• Allgemeine Beschreibung

  Class: dual threonine/tyrosine kinase; Treatment: melanoma with BRAF mutations; Other name: JTP-74057, GSK1120212; Oral bioavailability = 72%; Elimination half-life = 10 days; Protein binding = 97.4%

• Pharmakokinetik

  Trametinib has favorable pharmacokinetic properties: quick oral absorption with tmax of 0.5–1.5 h, long duration of action with effective t1/2 of 4 days, and elimination t1/2 of 10 days, as well as good oral bioavailability (72%). The unusual long half-life and good potency contribute a once-daily administration of just 2 mg, the lowest dosage of all the MEK inhibitors now in use (Table 2). Trametinib is metabolized predominantly via deacetylation to give 6, which subsequently undergoes hydroxylation to give 8 or glucuronidation to afford 7 (Fig. 4).
  

• Clinical Use

  Trametinib (GSK1120212) is an oral MEK inhibitor which has demonstrated excellent results in combination therapy for BRAF-mutated melanoma and is FDA approved in combination with BRAF inhibitors for that indication. Trametinib was evaluated initially as a single agent in KRAS mutant NSCLC in comparison with docetaxel and pemetrexed. Results as a single agent were not impressive, with an ORR of only 12% in these patients.

• target

  Primary target: MEK1/2

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antipsychotics: avoid with clozapine - increased risk of agranulocytosis.

• IC 50

  In vitro IC50's of MEK inhibitors:
  

• Stoffwechsel

  Metabolised mainly by deacetylation alone or in combination with mono-oxygenation. The deacetylated metabolite was further metabolised by glucuronidation. CYP3A4 oxidation is considered a minor pathway of metabolism. The deacetylation is mediated by the carboxyl-esterases 1b, 1c and 2, with possible contributions by other hydrolytic enzymes. Total dose recovery was low after a 10-day collection period (<50
  %) following administration of a single oral dose of radiolabelled trametinib, due to the long elimination
  Half-life. Trametinib was excreted mainly in the faeces (>80
  % of recovered radioactivity) and to a minor extent in urine (≤19
  %).

• Lager

  Store at -20°C

• Einzelnachweise

  1) Gilmartin?et al.?(2011),?GSK1120212 (JTP-74057) is an Inhibitor of MEK Activity and Activation with Favorable Pharmacokinetic Properties for Sustained In Vivo Pathway Inhibition; Clin. Cancer Res.?17?989 2) Abe?et al. (2011),?Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO solvate); ACS Med. Chem. Lett.?2?320 3) Allegrezza?et al.?(2016),?Trametinib Drives T-cell-Dependent Control of KRAS Tumors by Inhibiting Pathological Myelopoiesis; Cancer Res.?76?6253 4) Vella?et al.?(2014),?MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells; Cancer Immunol. Res.?2?351 5) Yamaguchi?et al.?(2012),?Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide; Inflamm. Res.?61?445

Trametinib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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