Peringatan Keamanan

The maximum asymptomatic dose in rats was 50 mg/kg MSDS. In animal studies, dacomitinib was shown to induce embryo-fetal toxicity, as demonstrated by an increased incidence of a post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45mg human dose following administration in rats during the period of organogenesis. On the other hand, dacomitinib was showed to lack a mutagenic potential in a bacterial reverse mutation assay, in human lymphocyte chromosome aberration assay and in clastogenic or aneugenic in vivo rat bone marrow micronucleus assay.FDA Label

The dose-limiting and overdose toxicities include stomatitis, rash, palmar-plantar erythrodysesthesia syndrome, dehydration, paronychia, and diarrhea. From these findings, the maximum tolerated dose (defined by the dose in which the dose-limiting toxicities did not exceed 33%) is 45 mg.A40012

Dacomitinib

DB11963

small molecule approved investigational

Deskripsi

Dacomitinib, designed as (2E)-N-16-4-(piperidin-1-yl) but-2-enamide, is an oral highly selective quinazalone part of the second-generation tyrosine kinase inhibitors which are characterized by the irreversible binding at the ATP domain of the epidermal growth factor receptor family kinase domains.A40009

Dacomitinib was developed by Pfizer Inc and approved by the FDA on September 27, 2018.L4810 Some evidence in the literature suggests the therapeutic potential of dacomitinib in the epithelial ovarian cancer modelA39624, although further investigations are needed.

Struktur Molekul 2D

Berat 469.939
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) Dacomitinib is reported to have a very large half-life of 70 hours.[T367]
Volume Distribusi The volume of distribution of dacomitinib was reported to be of 2415 L.[A40019]
Klirens (Clearance) The geometric apparent clearance of dacomitinib is 27.06 L/h.[A40019]

Absorpsi

Dacomitinib has shown a linear kinetics after single and multiple dose range studies. The absorption and distribution do not seem to be affected by food or the consumption of antacids. The peak plasma concentration after a dosage of 45 mg for 4 days is of 104 ng/ml.A40012 The reported AUC0-24h and tmax are of 2213 ng.h/mL and 6 hours, respectively. As well, following oral administration, the absolute oral bioavailability is 80% FDA Label.

Metabolisme

Dacomitinib presents an oxidative and conjugative metabolism marked mainly by the activity of glutathione and cytochrome P450 enzymes.A40012 After metabolism, its major circulating metabolite is an O-desmethyl dacomitinib form named PF-05199265.A40014 This metabolite has been shown to be formed by an oxidative step by CYP2D6 and to a smaller extent by CYP2C9. The following steps of the metabolism are mainly mediated by CYP3A4 for the formation of smaller metabolites.A40019 From these metabolic studies, it was shown that dacomitinib inhibited strongly the activities of CYP2D6.A40013

Rute Eliminasi

From the administered dose, 79% is recovered in feces, from which 20% represents the unmodified form of dacomitinib, and 3% is recovered in urine, from which <1% is represented by the unchanged form.A40019

Interaksi Makanan

5 Data
  • 1. Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of dacomitinib.
  • 2. Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of dacomitinib.
  • 3. Take at the same time every day.
  • 4. Take separate from antacids. Take dacomitinib at least 6 hours before or 10 hours after administering antacids.
  • 5. Take with or without food.

Interaksi Obat

1090 Data
Afatinib The serum concentration of Afatinib can be increased when it is combined with Dacomitinib.
Armodafinil The metabolism of Dacomitinib can be increased when combined with Armodafinil.
Modafinil The metabolism of Dacomitinib can be increased when combined with Modafinil.
Bosutinib The serum concentration of Bosutinib can be increased when it is combined with Dacomitinib.
Brentuximab vedotin The serum concentration of Brentuximab vedotin can be increased when it is combined with Dacomitinib.
Colchicine The serum concentration of Colchicine can be increased when it is combined with Dacomitinib.
Edoxaban The serum concentration of Edoxaban can be increased when it is combined with Dacomitinib.
Ledipasvir The serum concentration of Ledipasvir can be increased when it is combined with Dacomitinib.
Naloxegol The serum concentration of Naloxegol can be increased when it is combined with Dacomitinib.
Pazopanib The serum concentration of Pazopanib can be increased when it is combined with Dacomitinib.
Prucalopride The serum concentration of Prucalopride can be increased when it is combined with Dacomitinib.
Ranolazine The serum concentration of Ranolazine can be increased when it is combined with Dacomitinib.
Silodosin The excretion of Silodosin can be decreased when combined with Dacomitinib.
Topotecan The serum concentration of Topotecan can be increased when it is combined with Dacomitinib.
Phenytoin The metabolism of Dacomitinib can be increased when combined with Phenytoin.
Fosphenytoin The metabolism of Dacomitinib can be increased when combined with Fosphenytoin.
Everolimus The serum concentration of Everolimus can be increased when it is combined with Dacomitinib.
Rifaximin The serum concentration of Rifaximin can be increased when it is combined with Dacomitinib.
Irinotecan The risk or severity of neutropenia can be increased when Dacomitinib is combined with Irinotecan.
Metreleptin The metabolism of Dacomitinib can be increased when combined with Metreleptin.
Atomoxetine The metabolism of Atomoxetine can be decreased when combined with Dacomitinib.
Brexpiprazole The metabolism of Brexpiprazole can be decreased when combined with Dacomitinib.
Vortioxetine The metabolism of Vortioxetine can be decreased when combined with Dacomitinib.
Eliglustat The metabolism of Dacomitinib can be decreased when combined with Eliglustat.
Iloperidone The metabolism of Iloperidone can be decreased when combined with Dacomitinib.
Tetrabenazine The metabolism of Tetrabenazine can be decreased when combined with Dacomitinib.
Crizotinib The metabolism of Dacomitinib can be decreased when combined with Crizotinib.
Mirabegron The serum concentration of Dacomitinib can be increased when it is combined with Mirabegron.
Vincristine The excretion of Vincristine can be decreased when combined with Dacomitinib.
Doxorubicin The serum concentration of Doxorubicin can be increased when it is combined with Dacomitinib.
Lumacaftor The serum concentration of Dacomitinib can be decreased when it is combined with Lumacaftor.
Cyclosporine The metabolism of Dacomitinib can be decreased when combined with Cyclosporine.
Rolapitant The metabolism of Dacomitinib can be decreased when combined with Rolapitant.
Primaquine The metabolism of Dacomitinib can be decreased when combined with Primaquine.
Clobazam The serum concentration of Dacomitinib can be increased when it is combined with Clobazam.
Cimetidine The metabolism of Dacomitinib can be decreased when combined with Cimetidine.
Panobinostat The metabolism of Dacomitinib can be decreased when combined with Panobinostat.
Abiraterone The metabolism of Dacomitinib can be decreased when combined with Abiraterone.
Nicardipine The metabolism of Dacomitinib can be decreased when combined with Nicardipine.
Sulfaphenazole The metabolism of Dacomitinib can be decreased when combined with Sulfaphenazole.
Tranylcypromine The metabolism of Dacomitinib can be decreased when combined with Tranylcypromine.
Manidipine The metabolism of Dacomitinib can be decreased when combined with Manidipine.
Cholecalciferol The metabolism of Dacomitinib can be decreased when combined with Cholecalciferol.
Phenylbutyric acid The metabolism of Dacomitinib can be decreased when combined with Phenylbutyric acid.
Ritanserin The metabolism of Dacomitinib can be decreased when combined with Ritanserin.
Rhein The metabolism of Dacomitinib can be decreased when combined with Rhein.
Fluvoxamine The metabolism of Dacomitinib can be decreased when combined with Fluvoxamine.
Metoprolol The metabolism of Dacomitinib can be decreased when combined with Metoprolol.
Venlafaxine The metabolism of Dacomitinib can be decreased when combined with Venlafaxine.
Clozapine The serum concentration of Clozapine can be increased when it is combined with Dacomitinib.
Quinine The metabolism of Dacomitinib can be decreased when combined with Quinine.
Duloxetine The metabolism of Dacomitinib can be decreased when combined with Duloxetine.
Chlorpromazine The metabolism of Dacomitinib can be decreased when combined with Chlorpromazine.
Celecoxib The metabolism of Dacomitinib can be decreased when combined with Celecoxib.
Chloroquine The metabolism of Dacomitinib can be decreased when combined with Chloroquine.
Perhexiline The metabolism of Dacomitinib can be decreased when combined with Perhexiline.
Tegaserod The metabolism of Dacomitinib can be decreased when combined with Tegaserod.
Fusidic acid The metabolism of Dacomitinib can be decreased when combined with Fusidic acid.
Vilazodone The metabolism of Dacomitinib can be decreased when combined with Vilazodone.
Asunaprevir The metabolism of Dacomitinib can be decreased when combined with Asunaprevir.
Rucaparib The metabolism of Dacomitinib can be decreased when combined with Rucaparib.
Terbinafine The metabolism of Dacomitinib can be decreased when combined with Terbinafine.
Lumefantrine The metabolism of Dacomitinib can be decreased when combined with Lumefantrine.
Imipramine The metabolism of Dacomitinib can be decreased when combined with Imipramine.
Darifenacin The metabolism of Dacomitinib can be decreased when combined with Darifenacin.
Desipramine The metabolism of Dacomitinib can be decreased when combined with Desipramine.
Dosulepin The metabolism of Dacomitinib can be decreased when combined with Dosulepin.
Lorcaserin The metabolism of Dacomitinib can be decreased when combined with Lorcaserin.
Betrixaban The serum concentration of Betrixaban can be increased when it is combined with Dacomitinib.
Vemurafenib The serum concentration of Dacomitinib can be increased when it is combined with Vemurafenib.
Apalutamide The serum concentration of Dacomitinib can be decreased when it is combined with Apalutamide.
Pitolisant The serum concentration of Pitolisant can be increased when it is combined with Dacomitinib.
Isavuconazole The serum concentration of Dacomitinib can be increased when it is combined with Isavuconazole.
Isavuconazonium The serum concentration of Dacomitinib can be increased when it is combined with Isavuconazonium.
Deutetrabenazine The serum concentration of the active metabolites of Deutetrabenazine can be increased when Deutetrabenazine is used in combination with Dacomitinib.
Pravastatin Pravastatin may decrease the excretion rate of Dacomitinib which could result in a higher serum level.
Sulfasalazine Sulfasalazine may decrease the excretion rate of Dacomitinib which could result in a higher serum level.
Telmisartan Telmisartan may decrease the excretion rate of Dacomitinib which could result in a higher serum level.
Novobiocin Novobiocin may decrease the excretion rate of Dacomitinib which could result in a higher serum level.
Hesperetin Hesperetin may decrease the excretion rate of Dacomitinib which could result in a higher serum level.
Daidzin Daidzin may decrease the excretion rate of Dacomitinib which could result in a higher serum level.
Naringenin Naringenin may decrease the excretion rate of Dacomitinib which could result in a higher serum level.
Quercetin The metabolism of Dacomitinib can be decreased when combined with Quercetin.
Taurocholic acid Taurocholic acid may decrease the excretion rate of Dacomitinib which could result in a higher serum level.
Teriflunomide Teriflunomide may decrease the excretion rate of Dacomitinib which could result in a higher serum level.
Paritaprevir Paritaprevir may decrease the excretion rate of Dacomitinib which could result in a higher serum level.
Folic acid Dacomitinib may decrease the excretion rate of Folic acid which could result in a higher serum level.
Conjugated estrogens Dacomitinib may decrease the excretion rate of Conjugated estrogens which could result in a higher serum level.
Allopurinol Dacomitinib may decrease the excretion rate of Allopurinol which could result in a higher serum level.
Prazosin Dacomitinib may decrease the excretion rate of Prazosin which could result in a higher serum level.
Oxaliplatin Dacomitinib may decrease the excretion rate of Oxaliplatin which could result in a higher serum level.
Clofarabine Dacomitinib may decrease the excretion rate of Clofarabine which could result in a higher serum level.
Sumatriptan Dacomitinib may decrease the excretion rate of Sumatriptan which could result in a higher serum level.
Nitrofurantoin Dacomitinib may decrease the excretion rate of Nitrofurantoin which could result in a higher serum level.
Lamivudine Dacomitinib may decrease the excretion rate of Lamivudine which could result in a higher serum level.
Riluzole Dacomitinib may decrease the excretion rate of Riluzole which could result in a higher serum level.
Camptothecin Dacomitinib may decrease the excretion rate of Camptothecin which could result in a higher serum level.
Riociguat Dacomitinib may decrease the excretion rate of Riociguat which could result in a higher serum level.
Sofosbuvir Dacomitinib may decrease the excretion rate of Sofosbuvir which could result in a higher serum level.
Fimasartan Dacomitinib may decrease the excretion rate of Fimasartan which could result in a higher serum level.

Target Protein

Receptor tyrosine-protein kinase erbB-4 ERBB4
Receptor tyrosine-protein kinase erbB-2 ERBB2
Epidermal growth factor receptor EGFR

Referensi & Sumber

Artikel (PubMed)
  • PMID: 28646172
    Momeny M, Zarrinrad G, Moghaddaskho F, Poursheikhani A, Sankanian G, Zaghal A, Mirshahvaladi S, Esmaeili F, Eyvani H, Barghi F, Sabourinejad Z, Alishahi Z, Yousefi H, Ghasemi R, Dardaei L, Bashash D, Chahardouli B, Dehpour AR, Tavakkoly-Bazzaz J, Alimoghaddam K, Ghavamzadeh A, Ghaffari SH: Dacomitinib, a pan-inhibitor of ErbB receptors, suppresses growth and invasive capacity of chemoresistant ovarian carcinoma cells. Sci Rep. 2017 Jun 23;7(1):4204. doi: 10.1038/s41598-017-04147-0.
  • PMID: 23294134
    Brzezniak C, Carter CA, Giaccone G: Dacomitinib, a new therapy for the treatment of non-small cell lung cancer. Expert Opin Pharmacother. 2013 Feb;14(2):247-53. doi: 10.1517/14656566.2013.758714. Epub 2013 Jan 7.
  • PMID: 18089823
    Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T, Zhao F, Vincent PW, Naumov GN, Bradner JE, Althaus IW, Gandhi L, Shapiro GI, Nelson JM, Heymach JV, Meyerson M, Wong KK, Janne PA: PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 2007 Dec 15;67(24):11924-32. doi: 10.1158/0008-5472.CAN-07-1885.
  • PMID: 9751783
    Fry DW, Bridges AJ, Denny WA, Doherty A, Greis KD, Hicks JL, Hook KE, Keller PR, Leopold WR, Loo JA, McNamara DJ, Nelson JM, Sherwood V, Smaill JB, Trumpp-Kallmeyer S, Dobrusin EM: Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):12022-7.
  • PMID: 21220471
    Janne PA, Boss DS, Camidge DR, Britten CD, Engelman JA, Garon EB, Guo F, Wong S, Liang J, Letrent S, Millham R, Taylor I, Eckhardt SG, Schellens JH: Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res. 2011 Mar 1;17(5):1131-9. doi: 10.1158/1078-0432.CCR-10-1220. Epub 2011 Jan 10.
  • PMID: 22147075
    Bello CL, LaBadie RR, Ni G, Boutros T, McCormick C, Ndongo MN: The effect of dacomitinib (PF-00299804) on CYP2D6 activity in healthy volunteers who are extensive or intermediate metabolizers. Cancer Chemother Pharmacol. 2012 Apr;69(4):991-7. doi: 10.1007/s00280-011-1793-7. Epub 2011 Dec 7.
  • PMID: 30247945
    Sepulveda JM, Sanchez-Gomez P, Vaz Salgado MA, Gargini R, Balana C: Dacomitinib: an investigational drug for the treatment of glioblastoma. Expert Opin Investig Drugs. 2018 Oct;27(10):823-829. doi: 10.1080/13543784.2018.1528225. Epub 2018 Oct 5.
  • PMID: 28958502
    Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok TS: Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1454-1466. doi: 10.1016/S1470-2045(17)30608-3. Epub 2017 Sep 25.
Menampilkan 8 dari 12 artikel.
Textbook
  • Bethesda (2006). Drugs and Lactation Database. National Library of Medicine.

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