Krizotinib: Perbedaan antara revisi
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'''Krizotinib''' adalah obat antikanker yang digunakan untuk pengobatan karsinoma paru non-sel kecil (NSCLC).<ref name="Xalkori FDA label" /><ref name="Xalkori EPAR" /><ref name="FDA approval package">{{cite web | title=Drug Approval Package: Xalkori Capsules (crizotinib) NDA #202570 | website=U.S. [[Food and Drug Administration]] (FDA) | date=27 September 2011 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000TOC.cfm | access-date=18 April 2021 | archive-date=7 April 2021 | archive-url=https://web.archive.org/web/20210407110925/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000TOC.cfm | url-status=live }}</ref><ref>{{cite web|url= https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000SumR.pdf|title= Summary Review for Regulatory Action|date= 26 August 2011|website= U.S. [[Food and Drug Administration]] (FDA)|access-date= 19 April 2021|archive-date= 6 April 2021|archive-url= https://web.archive.org/web/20210406185359/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000SumR.pdf|url-status= live}}</ref>
==Kegunaan dalam medis==
Krizotinib diindikasikan untuk pengobatan kanker paru non-sel kecil (NSCLC) metastatik atau limfoma sel besar anaplastik sistemik (ALCL) yang kambuh atau refrakter, yang positif ALK.<ref name="Xalkori FDA label">{{cite web | title=Xalkori- crizotinib capsule | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a51b0de-47d6-455e-a94c-d2c737b04ff7 | access-date=18 April 2021 | archive-date=9 October 2021 | archive-url=https://web.archive.org/web/20211009140830/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a51b0de-47d6-455e-a94c-d2c737b04ff7 | url-status=live }}</ref><ref name="Xalkori EPAR">{{cite web | title=Xalkori EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/xalkori | access-date=18 April 2021 | archive-date=19 April 2021 | archive-url=https://web.archive.org/web/20210419003103/https://www.ema.europa.eu/en/medicines/human/EPAR/xalkori | url-status=live }}</ref>
Obat ini juga diindikasikan untuk pengobatan tumor miofibroblastik (IMT) positif kinase limfoma anaplastik inflamasi (ALK) yang tidak dapat direseksi, berulang, atau refrakter.<ref name="Xalkori FDA label" /><ref>{{cite press release | title=FDA approves crizotinib for ALK-positive inflammatory myofibroblastic tumor | website=U.S. [[Food and Drug Administration]] (FDA) | date=14 July 2022 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizotinib-alk-positive-inflammatory-myofibroblastic-tumor | access-date=14 July 2022 | archive-date=14 July 2022 | archive-url=https://web.archive.org/web/20220714194811/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizotinib-alk-positive-inflammatory-myofibroblastic-tumor | url-status=live }} {{PD-notice}}</ref>
==Mekanisme kerja==
[[File:2xp2.png|thumb|Kinase limfoma anaplastik manusia dalam kompleks dengan krizotinib. PDB {{PDBe|2xp2}}<ref name="pmid21812414">{{cite journal | vauthors = Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP | display-authors = 6 | title = Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK) | journal = Journal of Medicinal Chemistry | volume = 54 | issue = 18 | pages = 6342–63 | date = September 2011 | pmid = 21812414 | doi = 10.1021/jm2007613 }}</ref>]]
Krizotinib memiliki struktur aminopiridina, dan berfungsi sebagai penghambat [[kinase protein]] melalui pengikatan kompetitif dalam kantong pengikat ATP dari target kinase. Sekitar 4% pasien dengan karsinoma paru non-sel kecil mengalami penataan ulang [[kromosom]] yang menghasilkan gen fusi antara ''EML4'' ('protein terkait mikrotubulus echinodermata seperti 4') dan ''ALK'' ('Kinase limfoma anaplastik'), yang menghasilkan aktivitas [[kinase]] konstitutif yang berkontribusi terhadap [[karsinogenesis]] dan tampaknya mendorong [[fenotipe]] ganas. Aktivitas kinase dari protein fusi dihambat oleh krizotinib. Pasien dengan fusi gen ini biasanya adalah non-perokok muda yang tidak memiliki mutasi pada gen reseptor faktor pertumbuhan epidermal (EGFR) atau pada gen ''K-Ras''.<ref name=CME/><ref name=HemOncToday/> Jumlah kasus baru NSLC fusi ''ALK'' adalah sekitar 9.000 per tahun di AS dan sekitar 45.000 di seluruh dunia.<ref name=WSJ/><ref name=PfizerPress/>
Mutasi ALK dianggap penting dalam mendorong fenotipe ganas pada sekitar 15% kasus [[neuroblastoma]], suatu bentuk kanker sistem saraf tepi langka yang terjadi hampir secara eksklusif pada anak-anak yang sangat muda.<ref name='Janoueix'>{{cite journal | vauthors = Janoueix-Lerosey I, Schleiermacher G, Delattre O | title = Molecular pathogenesis of peripheral neuroblastic tumors | journal = Oncogene | volume = 29 | issue = 11 | pages = 1566–79 | date = March 2010 | pmid = 20101209 | doi = 10.1038/onc.2009.518 | doi-access = free }}</ref>
Krizotinib dianggap memberikan efeknya melalui modulasi pertumbuhan, migrasi, dan invasi sel ganas.<ref name="TrialNCT00585195"/><ref name='Christensen_2007'>{{cite journal | vauthors = Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G | display-authors = 6 | title = Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma | journal = Molecular Cancer Therapeutics | volume = 6 | issue = 12 Pt 1 | pages = 3314–22 | date = December 2007 | pmid = 18089725 | doi = 10.1158/1535-7163.MCT-07-0365 | doi-access = free }}</ref> Penelitian lain menunjukkan bahwa krizotinib mungkin juga bekerja melalui penghambatan [[angiogenesis]] pada tumor ganas.<ref name = "Zou_2007">{{cite journal | vauthors = Zou HY, Li Q, Lee JH, Arango ME, McDonnell SR, Yamazaki S, Koudriakova TB, Alton G, Cui JJ, Kung PP, Nambu MD, Los G, Bender SL, Mroczkowski B, Christensen JG | display-authors = 6 | title = An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms | journal = Cancer Research | volume = 67 | issue = 9 | pages = 4408–17 | date = May 2007 | pmid = 17483355 | doi = 10.1158/0008-5472.CAN-06-4443 | doi-access = free }}</ref>
==Masyarakat dan budaya==
===Status hukum===
Pada bulan Agustus 2011, [[Badan Pengawas Obat dan Makanan Amerika Serikat]] (FDA) menyetujui krizotinib untuk mengobati [[kanker paru-paru]] non-sel kecil stadium lanjut (lokal lanjut atau metastasis) tertentu yang mengekspresikan gen kinase limfoma anaplastik (ALK) yang abnormal.<ref name="FDA approval package" /> Persetujuan tersebut memerlukan uji molekuler pendamping untuk fusi EML4-ALK. Pada bulan Maret 2016, FDA menyetujui krizotinib pada kanker paru non-sel kecil positif ROS1.<ref>{{cite web|url=http://www.fiercepharma.com/pharma/nice-backs-pfizer-s-xalkori-after-squeezing-out-a-new-discount|title=NICE backs Pfizer's Xalkori after squeezing out a new discount – FiercePharma|date=18 August 2016|access-date=18 August 2016|archive-date=8 August 2020|archive-url=https://web.archive.org/web/20200808151550/https://www.fiercepharma.com/pharma/nice-backs-pfizer-s-xalkori-after-squeezing-out-a-new-discount|url-status=live}}</ref>
Pada bulan Oktober 2012, [[Badan Pengawas Obat Eropa]] (EMA) menyetujui penggunaan krizotinib untuk mengobati kanker paru-paru non-sel kecil yang mengekspresikan gen ALK yang abnormal.<ref name="Xalkori EPAR" /><ref>{{cite web|publisher=[[European Medicines Agency]]|title=Xalkori - EMEA/H/C/002489 - T/0059|year=2012|url=https://www.ema.europa.eu/documents/product-information/xalkori-epar-product-information_en.pdf|access-date=22 October 2018|archive-date=4 October 2018|archive-url=https://web.archive.org/web/20181004223130/https://www.ema.europa.eu/documents/product-information/xalkori-epar-product-information_en.pdf|url-status=live}}</ref>
==Penelitian==
===Kanker paru-paru===
Krizotinib menyebabkan tumor menyusut atau stabil pada 90% dari 82 pasien pembawa gen fusi ALK.<ref name=HemOncToday/><ref name=WSJ/> Tumor menyusut sedikitnya 30% pada 57% orang yang diobati.<ref name=WSJ/>
<ref>{{cite web |url=http://www.ascopost.com/articles/july-2010/novel-agent-demonstrates-striking-activity-in-alk-positive-nsclc |title=Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC |author=Helwick |year=2010 |url-status=dead |archive-url=https://web.archive.org/web/20110128120505/http://www.ascopost.com/articles/july-2010/novel-agent-demonstrates-striking-activity-in-alk-positive-nsclc |archive-date=28 January 2011 }} NB Fig 1.</ref> Sebagian besar menderita adenokarsinoma, dan tidak pernah merokok atau mantan perokok. Mereka telah menjalani pengobatan dengan rata-rata tiga obat lain sebelum menerima krizotinib, dan hanya 10% yang diharapkan merespons terapi standar.<ref name=HemOncToday/><ref name=MSNBC/> Mereka diberi 250 mg krizotinib dua kali sehari selama rata-rata enam bulan.<ref name=HemOncToday/> Sekitar 50% dari pasien ini mengalami sedikitnya satu efek samping seperti [[mual]], [[muntah]], atau [[diare]]. Beberapa respons terhadap krizotinib bertahan hingga 15 bulan.<ref name=MSNBC/>
Uji coba Fase III, PROFILE 1007,<ref name="urlwww.pfizer.com">{{cite web | url = http://www.pfizer.com/files/news/asco/crizotinib_fact_sheet.pdf | title = Crizotinib Clinical Trials – Currently Ongoing and/or Enrolling | publisher = Pfizer | work = Fact Sheet | access-date = 16 August 2014 | archive-date = 3 March 2016 | archive-url = https://web.archive.org/web/20160303231640/http://www.pfizer.com/files/news/asco/crizotinib_fact_sheet.pdf | url-status = live }}</ref> membandingkan krizotinib dengan kemoterapi lini kedua standar (pemetreksed atau [[dosetaksel]]) dalam pengobatan NSCLC ALK-positif.<ref name=ClinicalTrial1/><ref name=PfizerPress/><ref name=ClinicalTrial2/> Selain itu, uji coba fase 2, PROFILE 1005, mempelajari pasien yang memenuhi kriteria serupa yang telah menerima lebih dari satu lini kemoterapi sebelumnya.<ref name=PfizerPress/>
Pada bulan Februari 2016, studi fase III J-ALEX yang membandingkan alektinib dengan NSCLC metastatik ALK-positif krizotinib dihentikan lebih awal karena analisis sementara menunjukkan bahwa kelangsungan hidup bebas progresi lebih lama dengan alektinib.<ref>{{cite news|url=http://www.roche.com/inv-update-2016-02-10b-annex.pdf|title=Chugai's ALK Inhibitor "Alecensa" Trial Stopped Early for Benefit|publisher=Roche|date=February 2016|access-date=8 December 2017|archive-date=18 April 2016|archive-url=https://web.archive.org/web/20160418085455/http://www.roche.com/inv-update-2016-02-10b-annex.pdf|url-status=live}}</ref> Hasil ini dikonfirmasi dalam analisis tahun 2017.<ref name=FDA2017-11>{{cite news|url=https://www.healio.com/hematology-oncology/lung-cancer/news/online/%7Ba97a3d66-e12d-42a5-9b72-4d330b151aaf%7D/fda-approves-alecensa-for-alk--positive-metastatic-non-small-cell-lung-cancer|title=FDA approves Alecensa for ALK-positive metastatic non-small cell lung cancer|publisher=Healio|date=November 2017|access-date=8 December 2017|archive-date=9 December 2017|archive-url=https://web.archive.org/web/20171209044234/https://www.healio.com/hematology-oncology/lung-cancer/news/online/%7Ba97a3d66-e12d-42a5-9b72-4d330b151aaf%7D/fda-approves-alecensa-for-alk--positive-metastatic-non-small-cell-lung-cancer|url-status=live}}</ref>
===Limfoma===
Pada orang yang terkena limfoma sel besar anaplastik ALK+ kambuh atau refrakter, krizotinib menghasilkan tingkat respons objektif berkisar antara 65% hingga 90% dan tingkat kelangsungan hidup bebas progresi 3 tahun sebesar 60–75%. Tidak ada kekambuhan [[limfoma]] yang pernah diamati setelah 100 hari pertama pengobatan. Pengobatan harus dilanjutkan tanpa batas waktu saat ini.<ref>{{cite journal|vauthors=Gambacorti-Passerini C et al|title=Clinical Activity of Crizotinib In Advanced, Chemoresistant ALK+ Lymphoma Patients|year=2010| journal=Annual Meeting of the American Society of Hematology|location=Orlando, Florida}}</ref><ref>{{cite journal | vauthors = Gambacorti-Passerini C, Messa C, Pogliani EM | title = Crizotinib in anaplastic large-cell lymphoma | journal = The New England Journal of Medicine | volume = 364 | issue = 8 | pages = 775–6 | date = February 2011 | pmid = 21345110 | doi = 10.1056/NEJMc1013224 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Gambacorti Passerini C, Farina F, Stasia A, Redaelli S, Ceccon M, Mologni L, Messa C, Guerra L, Giudici G, Sala E, Mussolin L, Deeren D, King MH, Steurer M, Ordemann R, Cohen AM, Grube M, Bernard L, Chiriano G, Antolini L, Piazza R | display-authors = 6 | title = Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients | journal = Journal of the National Cancer Institute | volume = 106 | issue = 2 | pages = djt378 | date = February 2014 | pmid = 24491302 | doi = 10.1093/jnci/djt378 | doi-access = free }}</ref>
===Kanker lainnya===
Krizotinib juga sedang diuji dalam uji klinis neuroblastoma diseminata stadium lanjut.<ref name='NeuroblastomaTrial'>{{cite journal | vauthors = Wood AC, Laudenslager M, Haglund EA, Attiyeh EF, Pawel B, Courtright J, Plegaria J, Christensen JG, Maris JM, Mosse YP | title = Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066 | journal = J Clin Oncol | year = 2009 | volume = 27 | issue = 15s. suppl; abstr 10008b | pages = 10008b | doi = 10.1200/jco.2009.27.15_suppl.10008b | url = http://meeting.ascopubs.org/cgi/content/short/27/15S/10008b | archive-url = https://archive.today/20140816140343/http://meeting.ascopubs.org/cgi/content/short/27/15S/10008b | url-status = dead | archive-date = 16 August 2014 }}</ref>
==Referensi==
{{reflist|refs=
<ref name=ClinicalTrial1>{{ClinicalTrialsGov|NCT00932451|An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene}}</ref>
<ref name=CME>{{cite web | url = http://cme.medscape.com/viewarticle/720896_transcript | title = Maintenance Therapy for Non-Small Cell Lung Cancer | date = 12 May 2010 | publisher = MedscapeCME | access-date = 7 June 2010 | archive-date = 6 December 2012 | archive-url = https://archive.today/20121206015439/http://cme.medscape.com/viewarticle/720896_transcript | url-status = live }}</ref>
<ref name=HemOncToday>{{cite web | url = http://www.hemonctoday.com/article.aspx?rid=65251 | title = ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC | date = 5 June 2010 | publisher = HemOncToday | access-date = 7 June 2010 | archive-date = 6 April 2020 | archive-url = https://web.archive.org/web/20200406034739/http://www.hemonctoday.com/article.aspx?rid=65251 | url-status = live }}</ref>
<ref name=WSJ>{{cite news | url = https://www.wsj.com/articles/SB10001424052748704002104575291103764336126?mod=WSJ_WSJ_US_News_3 | title = Advances Come in War on Cancer | date = 7 June 2010 | publisher = The Wall Street Journal | access-date = 7 June 2010 | vauthors = Winslow R | archive-date = 9 October 2021 | archive-url = https://web.archive.org/web/20211009140831/https://www.wsj.com/articles/SB10001424052748704002104575291103764336126?mod=WSJ_WSJ_US_News_3 | url-status = live }}</ref>
<ref name=PfizerPress>{{cite press release | title = Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types | url = http://media.pfizer.com/files/news/press_releases/2010/asco_curtain_raiser_052010.pdf | publisher = Pfizer Oncology | date = 20 May 2010 | access-date = 7 June 2010 | url-status = dead | archive-url = https://web.archive.org/web/20100612203421/http://media.pfizer.com/files/news/press_releases/2010/asco_curtain_raiser_052010.pdf | archive-date = 12 June 2010 }}</ref>
<ref name=MSNBC>{{cite web | url = http://www.nbcnews.com/id/37527542 | title = Gene-based lung cancer drug shows promise | date = 7 May 2010 | work = NBC News | access-date = 7 June 2010}}{{dead link|date=August 2024|bot=medic}}{{cbignore|bot=medic}}</ref>
<ref name=ClinicalTrial2>{{ClinicalTrialsGov|NCT00932893|An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene}}</ref>
}}
== Pranala luar ==
* {{cite web | title=Crizotinib | work=NCI Drug Dictionary | publisher=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/crizotinib }}
* {{cite web | title=Crizotinib | website=National Cancer Institute | date=11 October 2011 | url=https://www.cancer.gov/about-cancer/treatment/drugs/crizotinib }}
* {{ClinicalTrialsGov|NCT00585195|A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer (PROFILE 1001)}}
* {{ClinicalTrialsGov|NCT00932893|An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene}}
* {{ClinicalTrialsGov|NCT00939770|Crizotinib in Treating Younger Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma}}
* {{ClinicalTrialsGov|NCT01154140|A Clinical Trial Testing The Efficacy Of Crizotinib Versus Standard Chemotherapy Pemetrexed Plus Cisplatin Or Carboplatin In Patients With ALK Positive Non Squamous Cancer Of The Lung (PROFILE 1014)}}
* {{ClinicalTrialsGov|NCT01979536|Brentuximab Vedotin or Crizotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II-IV Anaplastic Large Cell Lymphoma}}
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