Entrectinib

DB11986

small molecule approved investigational

Deskripsi

Entrectinib is a tropomyosin receptor tyrosine kinase (TRK) TRKA, TRKB, TRKC, proto-oncogene tyrosine-protein kinase ROS1, and anaplastic lymphoma kinase (ALK) inhibitor.L8081 It was approved by the FDA in August 2019 for use in the treatment of ROS1-positive metastatic non-small cell lung cancer and NTRK gene fusion positive solid tumors.L8207 Entrectinib's approved use is meant as a last line of therapy due to its accelerated approval based on early trial data. This therapy offers benefit over similar ALK inhibitors such as alectinib, ceritinib, and lorlatinib due to a wider range of targets.A183929

Struktur Molekul 2D

Berat 560.65
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) Entrectinib has a half-life of elimination of 20 h.[L8081] The active metabolite, M5, has a half-life of 40 h.
Volume Distribusi Entrectinib has an apparent volume of distribution of 551 L.[L8081] The active metabolite, M5, has an apparent volume of distribution of 81.1 L. Entrectinib is known to cross the blood-brain barrier.[A183797]
Klirens (Clearance) The apparent clearance of entrectinib is 19.6 L/h while the apparent clearance of the active metabolite M5 is 52.4 L/h.[L8081]

Absorpsi

Entrectinib has a Tmax of 4-5 h after administration of a single 600 mg dose.L8081 Food does not produce a significant effect on the extent of absorption.

Metabolisme

CYP3A4 is responsible for 76% of entrectinib metabolism in humans including metabolism to the active metabolite, M5.L8081 M5 has similar pharmacological activity to entrectinib and exists at approximately 40% of the steady state concentration of the parent drug. In rats, six in vivo metabolites have been identified including N-dealkylated, N-oxide, hydroxylated, and glucuronide conjugated metabolites.A183191

Rute Eliminasi

After a single radio-labeled dose of entrectinib, 83% of radioactivity was present in the feces and 3% in the urine.L8081 Of the dose in the feces, 36% was present as entrectinib and 22% as M5.

Interaksi Makanan

3 Data
  • 1. Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of entrectinib.
  • 2. Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of entrectinib.
  • 3. Take with or without food. Co-administration of food does not affect pharmacokinetics.

Interaksi Obat

878 Data
Afatinib The serum concentration of Afatinib can be increased when it is combined with Entrectinib.
Bosutinib The serum concentration of Bosutinib can be increased when it is combined with Entrectinib.
Brentuximab vedotin The serum concentration of Brentuximab vedotin can be increased when it is combined with Entrectinib.
Colchicine The serum concentration of Colchicine can be increased when it is combined with Entrectinib.
Edoxaban The serum concentration of Edoxaban can be increased when it is combined with Entrectinib.
Ledipasvir The serum concentration of Ledipasvir can be increased when it is combined with Entrectinib.
Naloxegol The serum concentration of Naloxegol can be increased when it is combined with Entrectinib.
Pazopanib The serum concentration of Pazopanib can be increased when it is combined with Entrectinib.
Prucalopride The serum concentration of Prucalopride can be increased when it is combined with Entrectinib.
Ranolazine The serum concentration of Ranolazine can be increased when it is combined with Entrectinib.
Silodosin The excretion of Silodosin can be decreased when combined with Entrectinib.
Topotecan The serum concentration of Topotecan can be increased when it is combined with Entrectinib.
Everolimus The serum concentration of Everolimus can be increased when it is combined with Entrectinib.
Rifaximin The serum concentration of Rifaximin can be increased when it is combined with Entrectinib.
Metreleptin The metabolism of Entrectinib can be increased when combined with Metreleptin.
Propacetamol The serum concentration of Propacetamol can be increased when it is combined with Entrectinib.
Vincristine The excretion of Vincristine can be decreased when combined with Entrectinib.
Doxorubicin The serum concentration of Doxorubicin can be increased when it is combined with Entrectinib.
Betrixaban The serum concentration of Betrixaban can be increased when it is combined with Entrectinib.
Tenofovir disoproxil The serum concentration of Tenofovir disoproxil can be increased when it is combined with Entrectinib.
Bisoprolol The serum concentration of Bisoprolol can be increased when it is combined with Entrectinib.
Canagliflozin The serum concentration of Canagliflozin can be increased when it is combined with Entrectinib.
Paritaprevir The serum concentration of Paritaprevir can be increased when it is combined with Entrectinib.
Velpatasvir The serum concentration of Velpatasvir can be increased when it is combined with Entrectinib.
Tezacaftor The serum concentration of Tezacaftor can be increased when it is combined with Entrectinib.
Valspodar The serum concentration of Valspodar can be increased when it is combined with Entrectinib.
Pravastatin The serum concentration of Pravastatin can be increased when it is combined with Entrectinib.
Morphine The serum concentration of Morphine can be increased when it is combined with Entrectinib.
Mannitol The serum concentration of Mannitol can be increased when it is combined with Entrectinib.
Clomifene The serum concentration of Clomifene can be increased when it is combined with Entrectinib.
Tegaserod The serum concentration of Tegaserod can be increased when it is combined with Entrectinib.
Sitagliptin The serum concentration of Sitagliptin can be increased when it is combined with Entrectinib.
Belinostat The serum concentration of Belinostat can be increased when it is combined with Entrectinib.
Ambrisentan The serum concentration of Ambrisentan can be increased when it is combined with Entrectinib.
Apixaban The serum concentration of Apixaban can be increased when it is combined with Entrectinib.
Odanacatib The serum concentration of Odanacatib can be increased when it is combined with Entrectinib.
Dolutegravir The serum concentration of Dolutegravir can be increased when it is combined with Entrectinib.
Sofosbuvir The serum concentration of Sofosbuvir can be increased when it is combined with Entrectinib.
Umeclidinium The serum concentration of Umeclidinium can be increased when it is combined with Entrectinib.
Technetium Tc-99m sestamibi The serum concentration of Technetium Tc-99m sestamibi can be increased when it is combined with Entrectinib.
Dasabuvir The serum concentration of Dasabuvir can be increased when it is combined with Entrectinib.
Ombitasvir The serum concentration of Ombitasvir can be increased when it is combined with Entrectinib.
Selexipag The serum concentration of Selexipag can be increased when it is combined with Entrectinib.
Grazoprevir The serum concentration of Grazoprevir can be increased when it is combined with Entrectinib.
Revefenacin The serum concentration of Revefenacin can be increased when it is combined with Entrectinib.
Elagolix The serum concentration of Elagolix can be increased when it is combined with Entrectinib.
Voxilaprevir The serum concentration of Voxilaprevir can be increased when it is combined with Entrectinib.
Omadacycline The serum concentration of Omadacycline can be increased when it is combined with Entrectinib.
Fedratinib The serum concentration of Entrectinib can be increased when it is combined with Fedratinib.
Grapiprant The serum concentration of Grapiprant can be increased when it is combined with Entrectinib.
Lusutrombopag The serum concentration of Lusutrombopag can be increased when it is combined with Entrectinib.
Pibrentasvir The serum concentration of Pibrentasvir can be increased when it is combined with Entrectinib.
Simvastatin The serum concentration of Simvastatin can be increased when it is combined with Entrectinib.
Enfortumab vedotin The serum concentration of Enfortumab vedotin can be increased when it is combined with Entrectinib.
Darolutamide The serum concentration of Darolutamide can be increased when it is combined with Entrectinib.
Lemborexant The serum concentration of Lemborexant can be increased when it is combined with Entrectinib.
Sildenafil The serum concentration of Sildenafil can be increased when it is combined with Entrectinib.
Fexofenadine The serum concentration of Fexofenadine can be increased when it is combined with Entrectinib.
Rivaroxaban The serum concentration of Rivaroxaban can be increased when it is combined with Entrectinib.
Lasmiditan The serum concentration of Lasmiditan can be increased when it is combined with Entrectinib.
Selumetinib The serum concentration of Selumetinib can be increased when it is combined with Entrectinib.
Ripretinib The serum concentration of Ripretinib can be increased when it is combined with Entrectinib.
Fostemsavir The serum concentration of Fostemsavir can be increased when it is combined with Entrectinib.
Belantamab mafodotin The serum concentration of Belantamab mafodotin can be increased when it is combined with Entrectinib.
Elbasvir The serum concentration of Elbasvir can be increased when it is combined with Entrectinib.
Voclosporin The serum concentration of Voclosporin can be increased when it is combined with Entrectinib.
Trilaciclib The serum concentration of Trilaciclib can be increased when it is combined with Entrectinib.
Daptomycin The serum concentration of Daptomycin can be increased when it is combined with Entrectinib.
Avanafil The serum concentration of Avanafil can be increased when it is combined with Entrectinib.
Tenofovir The serum concentration of Tenofovir can be increased when it is combined with Entrectinib.
Tivozanib The serum concentration of Tivozanib can be increased when it is combined with Entrectinib.
Loncastuximab tesirine The serum concentration of Loncastuximab tesirine can be increased when it is combined with Entrectinib.
Dabigatran etexilate The serum concentration of Dabigatran etexilate can be increased when it is combined with Entrectinib.
Sirolimus The serum concentration of Sirolimus can be increased when it is combined with Entrectinib.
Dactinomycin The serum concentration of Dactinomycin can be increased when it is combined with Entrectinib.
Temsirolimus The serum concentration of Temsirolimus can be increased when it is combined with Entrectinib.
Dacomitinib The serum concentration of Dacomitinib can be increased when it is combined with Entrectinib.
Cobimetinib The serum concentration of Cobimetinib can be increased when it is combined with Entrectinib.
Inotuzumab ozogamicin The risk or severity of QTc prolongation can be increased when Inotuzumab ozogamicin is combined with Entrectinib.
Pomalidomide The serum concentration of Pomalidomide can be increased when it is combined with Entrectinib.
Vinflunine The serum concentration of Vinflunine can be increased when it is combined with Entrectinib.
Talazoparib The serum concentration of Talazoparib can be increased when it is combined with Entrectinib.
Tolvaptan The serum concentration of Tolvaptan can be increased when it is combined with Entrectinib.
Bendamustine The serum concentration of Bendamustine can be increased when it is combined with Entrectinib.
Carfilzomib The serum concentration of Carfilzomib can be increased when it is combined with Entrectinib.
Binimetinib The serum concentration of Binimetinib can be increased when it is combined with Entrectinib.
Gemcitabine The serum concentration of Gemcitabine can be increased when it is combined with Entrectinib.
Axitinib The serum concentration of Axitinib can be increased when it is combined with Entrectinib.
Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Entrectinib.
Trastuzumab emtansine The serum concentration of Trastuzumab emtansine can be increased when it is combined with Entrectinib.
Cabergoline The serum concentration of Cabergoline can be increased when it is combined with Entrectinib.
Osimertinib The serum concentration of Osimertinib can be increased when it is combined with Entrectinib.
Etoposide The serum concentration of Etoposide can be increased when it is combined with Entrectinib.
Regorafenib The serum concentration of Regorafenib can be increased when it is combined with Entrectinib.
Nintedanib The metabolism of Entrectinib can be decreased when combined with Nintedanib.
Duvelisib The metabolism of Entrectinib can be decreased when combined with Duvelisib.
Tazemetostat The metabolism of Entrectinib can be decreased when combined with Tazemetostat.
Methysergide The metabolism of Entrectinib can be decreased when combined with Methysergide.
Albendazole The metabolism of Entrectinib can be decreased when combined with Albendazole.
Cephalexin The metabolism of Entrectinib can be decreased when combined with Cephalexin.

Target Protein

ALK tyrosine kinase receptor ALK
High affinity nerve growth factor receptor NTRK1
NT-3 growth factor receptor NTRK3
Proto-oncogene tyrosine-protein kinase ROS ROS1
BDNF/NT-3 growth factors receptor NTRK2
Tyrosine-protein kinase JAK2 JAK2
Activated CDC42 kinase 1 TNK2

Referensi & Sumber

Synthesis reference: US Patent 20190135784A1
Artikel (PubMed)
  • PMID: 31372957
    Al-Salama ZT, Keam SJ: Entrectinib: First Global Approval. Drugs. 2019 Aug 1. pii: 10.1007/s40265-019-01177-y. doi: 10.1007/s40265-019-01177-y.
  • PMID: 30050303
    Liu D, Offin M, Harnicar S, Li BT, Drilon A: Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. Ther Clin Risk Manag. 2018 Jul 20;14:1247-1252. doi: 10.2147/TCRM.S147381. eCollection 2018.
  • PMID: 30055343
    Attwa MW, Kadi AA, Alrabiah H, Darwish HW: LC-MS/MS reveals the formation of iminium and quinone methide reactive intermediates in entrectinib metabolism: In vivo and in vitro metabolic investigation. J Pharm Biomed Anal. 2018 Oct 25;160:19-30. doi: 10.1016/j.jpba.2018.07.032. Epub 2018 Jul 22.
  • PMID: 26457764
    Rolfo C, Ruiz R, Giovannetti E, Gil-Bazo I, Russo A, Passiglia F, Giallombardo M, Peeters M, Raez L: Entrectinib: a potent new TRK, ROS1, and ALK inhibitor. Expert Opin Investig Drugs. 2015;24(11):1493-500. doi: 10.1517/13543784.2015.1096344. Epub 2015 Oct 12.
  • PMID: 26939704
    Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, Ballinari D, Ciomei M, Texido G, Degrassi A, Avanzi N, Amboldi N, Saccardo MB, Casero D, Orsini P, Bandiera T, Mologni L, Anderson D, Wei G, Harris J, Vernier JM, Li G, Felder E, Donati D, Isacchi A, Pesenti E, Magnaghi P, Galvani A: Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Mol Cancer Ther. 2016 Apr;15(4):628-39. doi: 10.1158/1535-7163.MCT-15-0758. Epub 2016 Mar 3.
  • PMID: 30425456
    Pacenta HL, Macy ME: Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma. Drug Des Devel Ther. 2018 Oct 23;12:3549-3561. doi: 10.2147/DDDT.S147384. eCollection 2018.

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