Peringatan Keamanan

There is no information regarding the acute toxicity (LD50) of trametinib. The highest doses of trametinib evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on two consecutive days, followed by 3 mg once daily. Out of seven patients treated on one of these two schedules, two patients experienced retinal pigment epithelial detachments.L45558 In clinical trials with trametinib monotherapy, one case of accidental overdose was reported from a single dose of 4 mg: no adverse events were reported in this event.L45583 Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of drug overdose.L45558

Trametinib

DB08911

small molecule approved

Deskripsi

Trametinib is an orally bioavailable mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 inhibitor.A258298,A258293 It was first approved by the FDA in May 2013 for the treatment of melanoma.A258298 It was later approved by Health Canada on July 18, 2013 L45588 and by the European Commission on June 30, 2014.L45583 Trametinib is currently approved to treat a variety of cancers with BRAF mutations, such as non-small cell lung cancer and thyroid cancer, as monotherapy or in combination with dabrafenib, a BRAF inhibitor, for improved therapeutic efficacy. Originally developed by Japan Tobacco, trametinib was initially investigated for treating inflammation, but further studies for this indication were not pursued.A258298

Struktur Molekul 2D

Berat 615.3948
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The estimated elimination half-life is 3.9 to 4.8 days.[L45558]
Volume Distribusi The apparent volume of distribution (V<sub>c</sub>/F) is 214 L.[L45558]
Klirens (Clearance) The apparent clearance is 4.9 L/h.[L45558]

Absorpsi

Following oral administration, trametinib is rapidly and readily absorbed.A258323 The absorption was examined in patients with solid tumours and BRAF V600 mutation-positive metastatic melanoma. Following the administration of trametinib tablets 0.125 mg (0.0625 times the approved recommended adult dosage) to 4 mg (2 times the approved recommended adult dosage) daily, both Cmax and AUC increased dose-proportionally. Intersubject variability in AUC and Cmax at steady state is 22% and 28%, respectively.L45558 Trametinib accumulates with daily repeat dosing with a mean accumulation ratio of 6.0 at 2 mg once daily dose. Steady-state was achieved by Day 15.L45583 The mean absolute bioavailability of trametinib is 72% for oral tablets and 81% for oral solution. The Tmax is 1.5 hours. A high-fat, high-calorie meal (approximately 1000 calories) decreased trametinib AUC by 24% and Cmax by 70%, and delayed Tmax by approximately four hours as compared with fasted conditions.L45558

Metabolisme

Trametinib predominantly undergoes deacetylation mediated by carboxylesterases (i.e., carboxylesterase 1b/c and 2) and other hydrolytic enzymes. The deacetylated metabolite may further be glucuronidated.L45583 In vitro findings suggest that deacetylation may also be accompanied by mono-oxygenation,L45558 hydroxylation, and glucuronidation.A258323 CYP3A4-mediated oxidation is a minor pathway.L45583 Four metabolites (M1/2/3/4) have been characterized in patients with advanced cancers. In vitro, the M1 and M3 metabolites demonstrated approximately equal or 10-fold less potent phospho-MEK1-inhibiting activity than the parent compound.A258323 Following a single dose of 14C-trametinib, approximately 50% of circulating radioactivity represented the parent compound. According to findings from metabolite profiling after repeat dosing of trametinib, unchanged parent drug accounted for greater than or equal to 75% of drug-related material in plasma.L45558

Rute Eliminasi

Following oral administration of 14C-trametinib, greater than 80% of excreted radioactivity was recovered in the feces while less than 20% of excreted radioactivity was recovered in the urine with less than 0.1% of the excreted dose as the parent molecule.L45558

Interaksi Makanan

1 Data
  • 1. Take separate from meals. Take at least 1 hour before or at least 2 hours after a meal. A high-fat, high-calorie meal decreases trametinib AUC and Cmax, and delays Tmax.

Interaksi Obat

761 Data
Enzalutamide Enzalutamide may decrease the excretion rate of Trametinib which could result in a higher serum level.
Ifosfamide Ifosfamide may decrease the excretion rate of Trametinib which could result in a higher serum level.
Warfarin Trametinib may decrease the excretion rate of Warfarin which could result in a higher serum level.
Dabrafenib The risk or severity of adverse effects can be increased when Trametinib is combined with Dabrafenib.
Torasemide Torasemide may increase the excretion rate of Trametinib which could result in a lower serum level and potentially a reduction in efficacy.
Sulfadiazine Sulfadiazine may decrease the excretion rate of Trametinib which could result in a higher serum level.
Rosiglitazone Rosiglitazone may decrease the excretion rate of Trametinib which could result in a higher serum level.
Celecoxib Celecoxib may decrease the excretion rate of Trametinib which could result in a higher serum level.
Piroxicam Piroxicam may decrease the excretion rate of Trametinib which could result in a higher serum level.
Diclofenac Diclofenac may decrease the excretion rate of Trametinib which could result in a higher serum level.
Chloroquine Chloroquine may decrease the excretion rate of Trametinib which could result in a higher serum level.
Verapamil Verapamil may decrease the excretion rate of Trametinib which could result in a higher serum level.
Mycophenolate mofetil Mycophenolate mofetil may decrease the excretion rate of Trametinib which could result in a higher serum level.
Estradiol Estradiol may decrease the excretion rate of Trametinib which could result in a higher serum level.
Naproxen Naproxen may decrease the excretion rate of Trametinib which could result in a higher serum level.
Almotriptan Almotriptan may decrease the excretion rate of Trametinib which could result in a higher serum level.
Ibuprofen Ibuprofen may decrease the excretion rate of Trametinib which could result in a higher serum level.
Tolbutamide Tolbutamide may decrease the excretion rate of Trametinib which could result in a higher serum level.
Ketamine Ketamine may decrease the excretion rate of Trametinib which could result in a higher serum level.
Sitagliptin Sitagliptin may decrease the excretion rate of Trametinib which could result in a higher serum level.
Aminophenazone Aminophenazone may decrease the excretion rate of Trametinib which could result in a higher serum level.
Antipyrine Antipyrine may decrease the excretion rate of Trametinib which could result in a higher serum level.
Benzyl alcohol The risk or severity of methemoglobinemia can be increased when Trametinib is combined with Benzyl alcohol.
Vortioxetine Trametinib may decrease the excretion rate of Vortioxetine which could result in a higher serum level.
Propacetamol Propacetamol may decrease the excretion rate of Trametinib which could result in a higher serum level.
Testosterone cypionate Trametinib may decrease the excretion rate of Testosterone cypionate which could result in a higher serum level.
Testosterone enanthate Trametinib may decrease the excretion rate of Testosterone enanthate which could result in a higher serum level.
Testosterone undecanoate Trametinib may decrease the excretion rate of Testosterone undecanoate which could result in a higher serum level.
Estradiol acetate Trametinib may decrease the excretion rate of Estradiol acetate which could result in a higher serum level.
Estradiol cypionate Trametinib may decrease the excretion rate of Estradiol cypionate which could result in a higher serum level.
Estradiol dienanthate Trametinib may decrease the excretion rate of Estradiol dienanthate which could result in a higher serum level.
Estradiol valerate Trametinib may decrease the excretion rate of Estradiol valerate which could result in a higher serum level.
Ketorolac Ketorolac may decrease the excretion rate of Trametinib which could result in a higher serum level.
Dexibuprofen Dexibuprofen may decrease the excretion rate of Trametinib which could result in a higher serum level.
Amitriptyline Amitriptyline may decrease the excretion rate of Trametinib which could result in a higher serum level.
Finerenone Finerenone may increase the excretion rate of Trametinib which could result in a lower serum level and potentially a reduction in efficacy.
Apalutamide Trametinib may decrease the excretion rate of Apalutamide which could result in a higher serum level.
Icosapent Icosapent may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefotiam Cefotiam may decrease the excretion rate of Trametinib which could result in a higher serum level.
Mesalazine Mesalazine may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefmenoxime Cefmenoxime may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefmetazole Cefmetazole may decrease the excretion rate of Trametinib which could result in a higher serum level.
Pamidronic acid Pamidronic acid may decrease the excretion rate of Trametinib which could result in a higher serum level.
Tenofovir disoproxil Tenofovir disoproxil may decrease the excretion rate of Trametinib which could result in a higher serum level.
Indomethacin Indomethacin may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cidofovir Cidofovir may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefpiramide Cefpiramide may decrease the excretion rate of Trametinib which could result in a higher serum level.
Ceftazidime Ceftazidime may decrease the excretion rate of Trametinib which could result in a higher serum level.
Loracarbef Loracarbef may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefalotin Cefalotin may decrease the excretion rate of Trametinib which could result in a higher serum level.
Nabumetone Nabumetone may decrease the excretion rate of Trametinib which could result in a higher serum level.
Tenoxicam Tenoxicam may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefotaxime Cefotaxime may decrease the excretion rate of Trametinib which could result in a higher serum level.
Tolmetin Tolmetin may decrease the excretion rate of Trametinib which could result in a higher serum level.
Foscarnet Foscarnet may decrease the excretion rate of Trametinib which could result in a higher serum level.
Rofecoxib Rofecoxib may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cephalexin Cephalexin may decrease the excretion rate of Trametinib which could result in a higher serum level.
Fenoprofen Fenoprofen may decrease the excretion rate of Trametinib which could result in a higher serum level.
Valaciclovir Valaciclovir may decrease the excretion rate of Trametinib which could result in a higher serum level.
Valdecoxib Valdecoxib may decrease the excretion rate of Trametinib which could result in a higher serum level.
Sulindac Sulindac may decrease the excretion rate of Trametinib which could result in a higher serum level.
Bacitracin Bacitracin may decrease the excretion rate of Trametinib which could result in a higher serum level.
Amphotericin B Amphotericin B may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cephaloglycin Cephaloglycin may decrease the excretion rate of Trametinib which could result in a higher serum level.
Flurbiprofen Flurbiprofen may decrease the excretion rate of Trametinib which could result in a higher serum level.
Adefovir dipivoxil Adefovir dipivoxil may decrease the excretion rate of Trametinib which could result in a higher serum level.
Etodolac Etodolac may decrease the excretion rate of Trametinib which could result in a higher serum level.
Acyclovir Acyclovir may decrease the excretion rate of Trametinib which could result in a higher serum level.
Sulfasalazine Sulfasalazine may decrease the excretion rate of Trametinib which could result in a higher serum level.
Phenylbutazone Phenylbutazone may decrease the excretion rate of Trametinib which could result in a higher serum level.
Carprofen Carprofen may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefaclor Cefaclor may decrease the excretion rate of Trametinib which could result in a higher serum level.
Diflunisal Diflunisal may decrease the excretion rate of Trametinib which could result in a higher serum level.
Ceforanide Ceforanide may decrease the excretion rate of Trametinib which could result in a higher serum level.
Salicylic acid Salicylic acid may decrease the excretion rate of Trametinib which could result in a higher serum level.
Meclofenamic acid Meclofenamic acid may decrease the excretion rate of Trametinib which could result in a higher serum level.
Acetylsalicylic acid Acetylsalicylic acid may decrease the excretion rate of Trametinib which could result in a higher serum level.
Carboplatin Carboplatin may decrease the excretion rate of Trametinib which could result in a higher serum level.
Oxaprozin Oxaprozin may decrease the excretion rate of Trametinib which could result in a higher serum level.
Ketoprofen Ketoprofen may decrease the excretion rate of Trametinib which could result in a higher serum level.
Balsalazide Balsalazide may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefditoren Cefditoren may decrease the excretion rate of Trametinib which could result in a higher serum level.
Atazanavir Atazanavir may decrease the excretion rate of Trametinib which could result in a higher serum level.
Colistimethate Colistimethate may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefuroxime Cefuroxime may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefapirin Cefapirin may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefadroxil Cefadroxil may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefprozil Cefprozil may decrease the excretion rate of Trametinib which could result in a higher serum level.
Ceftriaxone Ceftriaxone may decrease the excretion rate of Trametinib which could result in a higher serum level.
Olsalazine Olsalazine may decrease the excretion rate of Trametinib which could result in a higher serum level.
Lumiracoxib Lumiracoxib may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefamandole Cefamandole may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefazolin Cefazolin may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefonicid Cefonicid may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefoperazone Cefoperazone may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefotetan Cefotetan may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefoxitin Cefoxitin may decrease the excretion rate of Trametinib which could result in a higher serum level.
Ceftizoxime Ceftizoxime may decrease the excretion rate of Trametinib which could result in a higher serum level.
Cefradine Cefradine may decrease the excretion rate of Trametinib which could result in a higher serum level.
Magnesium salicylate Magnesium salicylate may decrease the excretion rate of Trametinib which could result in a higher serum level.

Target Protein

Dual specificity mitogen-activated protein kinase kinase 1 MAP2K1
Dual specificity mitogen-activated protein kinase kinase 2 MAP2K2

Referensi & Sumber

Artikel (PubMed)
  • PMID: 23432625
    Salama AK, Kim KB: Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013 Apr;14(5):619-27. doi: 10.1517/14656566.2013.770475. Epub 2013 Feb 23.
  • PMID: 22805291
    Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, DeMarini DJ, Cox DS, Xu Y, Morris SR, Peddareddigari VG, Le NT, Hart L, Bendell JC, Eckhardt G, Kurzrock R, Flaherty K, Burris HA 3rd, Messersmith WA: Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012 Aug;13(8):773-81. doi: 10.1016/S1470-2045(12)70270-X. Epub 2012 Jul 16.
  • PMID: 24756797
    Zeiser R: Trametinib. Recent Results Cancer Res. 2014;201:241-8. doi: 10.1007/978-3-642-54490-3_15.
  • PMID: 23846731
    Wright CJ, McCormack PL: Trametinib: first global approval. Drugs. 2013 Jul;73(11):1245-54. doi: 10.1007/s40265-013-0096-1.
  • PMID: 23971497
    Ho MY, Morris MJ, Pirhalla JL, Bauman JW, Pendry CB, Orford KW, Morrison RA, Cox DS: Trametinib, a first-in-class oral MEK inhibitor mass balance study with limited enrollment of two male subjects with advanced cancers. Xenobiotica. 2014 Apr;44(4):352-68. doi: 10.3109/00498254.2013.831143. Epub 2013 Aug 23.

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