I-ALK-Positive Lung Cancer Drug "Ceritinib (LDK378)" -AASraw
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Ceritinib

 

    1. I-Ceritinib yamkelwe ukuze isetyenziswe kwi-EU
    2. Inkcazo yeCeritinib
    3. Isebenza njani iCeritinib yokuNyanga i-NSCLC?
    4. Njani malunga nokuSebenzisa iZonyango kwiCeritinib?
    5. Ungayigcina njani iCeritinib (LDK378)?
    6. Zithini iziphumo ebezingalindelekanga zeCeritinib?
    7. Zeziphi ezinye izibonelelo zeCeritinib eziye zabonakaliswa kwizifundo?
    8. I-Ceritinib ifumana Ukwamkelwa komgangatho wokuqala we-FDA kwi-ALK-Positive Lung Cancer

 

I-Ceritinib yavunywa ukuba isetyenziswe kwi-EU

I-Ceritinib (i-CAS: 1032900-25-6) ibonakalisiwe iyasebenza ekunyangeni abaguli abanesifo esiqhubele phambili ngexesha okanye emva nje konyango icrizotinib kwaye ngoku banokhetho olunqongopheleyo kunyango, kunye nezigulana ezingakhange zinyangwe ngaphambili. Ngokumalunga nokhuseleko, iziphumo ezibi neCeritinib ngokubanzi zibonakala zinokulawulwa.

I-Arhente yamayeza yaseYurophu ke ngoko igqibe ekubeni izibonelelo zeCeritinib zingaphezulu kobungozi bayo kwaye yacebisa ukuba yamkelwe ukuze isetyenziswe kwi-EU.

UCeritinib wayeqale wanikwa 'ukuvunywa okunemiqathango' kuba kwakukhona ubungqina obungaphezulu bokuza ngeli yeza. Njengokuba inkampani ibonelele ngolwazi olongezelelekileyo oluyimfuneko, ugunyaziso lutshintshiwe ukusuka kwimeko enemvume epheleleyo.

Kuya kufuneka unomdla ngale mveliso, makhe sifunde ngakumbi malunga noku Ceritinib:

 

Inkcazo yeCeritinib

I-Ceritinib isetyenziselwa unyango lwabantu abadala abane-anaplastic lymphoma kinase (ALK) -imetastatic efanelekileyo umhlaza wemiphunga ongekho mncinci (NSCLC) emva kokusilela (kokubini kukunganyangeki okanye ukunganyamezelani) kunyango lwangaphambili lwe-crizotinib. Phantse i-4% yezigulana ezine-NSCLC zinokuhlengahlengiswa kwakhona kwe-chromosomal eyenza i-fusion gene phakathi kwe-EML4 (echinoderm microtubule-related protein-like 4) kunye ne-ALK (anaplastic lymphoma kinase), ekhokelela kwimisebenzi ye-kinase enegalelo kwi-carcinogenesis kwaye ibonakala iqhuba i-phenotype enobungozi.

I-Ceritinib inefuthe lonyango ngokuthintela i-autophosphorylation ye-ALK, phosphorylation ye-ALK-Mediated ye-protein esezantsi ye-STAT3, kunye nokwanda kweeseli zomhlaza ezixhomekeke kwi-ALK. Ukulandela unyango nge-crizotinib (isizukulwana sokuqala se-ALK inhibitor), uninzi lwamathumba lukhulisa ukunganyangeki ngamachiza ngenxa yotshintsho kwizintsalela eziphambili zomgcini-masango we-enzyme. Oku kwenzeka kwakhokelela kuphuhliso lwenoveli yesibini-inhibitors ye-ALK inhibitors efana ne-ceritinib yokoyisa ukumelana ne-crizotinib. I-FDA yamkele i-ceritinib ngo-Epreli ka-2014 ngenxa yenqanaba lokuphendula eliphezulu ngokumangalisayo (iipesenti ezingama-56) ngokubhekisele kwizicwili ezinganyangekiyo kwi-crizotinib kwaye iyichonge njengeziyobisi.

 

Isebenza njani iCeritinib yokuNyanga i-NSCLC?

I-Ceritinib sisithinteli esikhethiweyo kunye esinamandla se-anaplastic lymphoma kinase (ALK). Kwimizimba yesiqhelo, Imisebenzi ye-ALK njengenyathelo eliphambili kuphuhliso kunye nokusebenza kwenkqubo yemithambo-luvo. Nangona kunjalo, ukuhanjiswa kwe-chromosomal kunye nokudibana kubangela ukuba ifom ye-ALK inyanzeliswa kukuqhubela phambili kwe-NSCLC. Ngenxa yokuba i-ceritinib ithathwa njengonyango lomhlaza ekujoliswe kulo, uvavanyo oluvunyiweyo lwe-FDA luyafuneka ukumisela ukuba zeziphi izigulana ezingabagqatswa be-ceritinib. Olu vavanyo, oluveliswe nguRoche, yiVENTANA ALK (D5F3) CDx Assay kwaye isetyenziselwa ukuchonga abaguli abane-ALK-positive NSCLC abaza kuxhamla kunyango lwe-ceritinib.

I-AASraw ngumenzi wobugcisa beCeritinib.

Nceda ucofe apha ngolwazi locaphulo: Unxibelelwano nathi

 

Njani malunga nokuSebenzisa iZonyango kwiCeritinib?

I-Ceritinib (LDK378) sisiyobisi esisetyenziselwa ukunyanga umhlaza wamaphaphu ongekho mncinci osasazeke kwamanye amalungu omzimba kwaye une-lymphoma kinase (ALK) elungileyo. Kuyafundwa kunyango lwezinye iintlobo zomhlaza. I-Ceritinib ibhloka iproteni eyenziwe luhlobo lwe-ALK. Ukuthintela le protein kunokumisa ukukhula kunye nokusasazeka kweeseli zomhlaza. I-Ceritinib luhlobo lwe-tyrosine kinase inhibitor.

 

Ceritinib

 

Ungayigcina njani iCeritinib (LDK378)?

Gcina iCeritinib (LDK378) kwisikhongozeli esangena, sivalekile, kwaye singafikeleleki ebantwaneni. Yigcine kubushushu begumbi kwaye kude nokukhanya, ubushushu obuninzi kunye nokufuma (hayi kwigumbi lokuhlambela).

Amayeza angafunekiyo kufuneka achithwe ngeendlela ezizodwa zokuqinisekisa ukuba izilwanyana zasekhaya, abantwana kunye nabanye abantu abanakuzisebenzisa. Nangona kunjalo, akufuneki ugungxule iCeritinib (LDK378) ezantsi kwindlu yangasese. Endaweni yoko, eyona ndlela yokulahla amayeza akho yinkqubo yokubuyisa amayeza. Thetha kumachiza wakho okanye unxibelelane nesebe lakho lenkunkuma / lokurisayikilisha ukuze ufunde malunga neenkqubo zokubuyisa kwindawo ohlala kuyo. Bona i Ukulahlwa okuKhuselekileyo kwe-FDA yeWebhusayithi yamayeza ngolwazi oluthe kratya ukuba awunakho ukufikelela kwinkqubo yokubuyisa.

Kubalulekile ukugcina onke amayeza angabonakaliyo kunye nokufikelela kubantwana njengezikhonkwane ezininzi (ezifana neepilisi zeveki zeeveki kunye nezokwamahla, i-creams, i-patches, kunye ne-inhalers) abaxhomeki abantwana kunye nabantwana abancinci bangabavula ngokulula. Ukukhusela abantwana abancinci besetyhefu, soloko uvale iifake zokuphepha kwaye ubeke ngokukhawuleza loo mayeza kwindawo ekhuselekileyo - enye ephakanyisiwe kwaye ingabikho emehlweni abo kwaye ifinyelele.

 

Zithini iziphumo ebezingalindelekanga zeCeritinib? 

Izinto ezibalulekileyo ekufuneka uzikhumbule malunga neziphumo ebezingalindelekanga ze-ceritinib:

Abantu abaninzi abazifumani zonke iziphumo ebezingalindelekanga ezidwelisiweyo.

Iziphumo ebezingalindelekanga zihlala ziqikelelwa ngokokubonakala kwazo kunye nobude bexesha.

Effects Iziphumo ebezingalindelekanga zihlala zibuyela umva kwaye ziya kuphela emva kokuba unyango lugqityiwe.

▪ Zininzi iindlela zokunceda ukunciphisa okanye ukuthintela iziphumo ebezingalindelekanga.

▪ Akukho budlelwane phakathi kobukho okanye ubuzaza beziphumo ebezingalindelekanga kunye nokusebenza kweyeza.

 

Iziphumo ebezingalindelekanga zixhaphakile (zenzeka ngaphezulu kwe-30%) kwizigulana ezithatha i-ceritinib:

▪ Urhudo

▪ IHemoglobin yehla

▪ Ukunyuka kwee-enzymes zesibindi

▪ Isicaphucaphu

▪ Ukuhlanza

▪ Ukwanda kwe-creatinine

▪ Intlungu esiswini

▪ Ukudinwa

▪ Iswekile yenyuka

▪ Ukuhla kwephosphate

▪ Ukunciphisa ukutya

I-AASraw ngumenzi wobugcisa beCeritinib.

Nceda ucofe apha ngolwazi locaphulo: Unxibelelwano nathi

 

Ezi ziphumo zingalindelekanga (ezenzeka malunga ne-10-29%) yezigulana ezifumana i-ceritinib:

▪ Ukuqunjelwa

▪ ILipase inyukile

▪ Isifo sokudinwa kwemiqala (Ukutsha kwentliziyo, idyspepsia, idysphagia)

▪ Irhashalala

▪ I-Bilirubin (iyonke) inyukile

Isiphumo esibi, kodwa esingaqhelekanga kakhulu se-ceritinib yi-pneumonitis (ukudumba kwemiphunga). Xa le mpembelelo yecala yenzekile, yayihlala ihamba nobunzima bokuphefumla ngokukhohlela okanye umkhuhlane ophantsi ofuna ukulaliswa esibhedlele. Iimpawu zinokufana nezo mpawu zomhlaza wemiphunga. Nxibelelana nomboneleli wakho wezempilo kwangoko ukuba unayo nayiphi na impawu ezintsha okanye eziba mandundu.

Olunye uhlangothi olubi kodwa aluqhelekanga kakhulu lwe-ceritinib lutshintsho lwe-EKG. Ayizizo zonke iziphumo ebezingalindelekanga ezidweliswe apha ngasentla. Ezinye ezinqabileyo (ezenzeka ngaphantsi kwe-10% yezigulana) azidweliswanga apha. Nangona kunjalo, kuya kufuneka usoloko umazisa umboneleli wakho wezempilo ukuba ufumana naziphi na iimpawu ezingaqhelekanga.

 

Ceritinib

 

Zeziphi ezinye izibonelelo zeCeritinib eziye zabonakaliswa kwizifundo?

Kwezi zifundo zibini, kubandakanya abaguli abangama-303, iyeza alifaniswa nolunye unyango. Impendulo kunyango yavavanywa kusetyenziswa isikeni somzimba kunye neendlela ezisemgangathweni ezisetyenziselwa izilonda eziqinileyo, impendulo epheleleyo xa isigulana singenazo iimpawu zomhlaza. Kwisifundo esinye i-56% yezigulana ezinikwe i-ceritinib (i-92 ye-163) yathathelwa ingqalelo ngonyango lokunyanga ukuba ibonakalise impendulo epheleleyo okanye inxenye kunyango. Ubude obuqhelekileyo bokuphendula yayiziinyanga eziyi-8.3. Kwisifundo sesibini, ireyithi yokuphendula iyonke yayiyi-41% (i-57 yeziguli ezili-140) kwaye ubude bempendulo bebuyinyanga ezili-10.6.

Kwisifundo sesithathu kwizigulana ezingama-231, i-ceritinib yafaniswa ne-chemotherapy esemgangathweni (amayeza anyanga umhlaza). Iziphumo zabonisa ukuba abaguli abanikwe i-ceritinib baphila i-avareji yeenyanga ezi-5.4 ngaphandle kokuba isifo sabo siba sibi (ukuqhubeka kokungabikho kokuqhubela phambili) xa kuthelekiswa neenyanga eziyi-1.6 kwizigulana ezinikwe ichemotherapy esemgangathweni.

Ceritinib ikwabonakalise ukuba iyasebenza ekunyangeni abaguli abangakhange banyangwe ngaphambili kwisifundo kwizigulana ezingama-376. Izigulana ezinikwe i-ceritinib zihlala i-avareji yeenyanga ezili-16.6 ngaphandle kokuba isifo sazo siba sibi ngokuthelekiswa neenyanga eziyi-8.1 kwizigulana ezinikwe ichemotherapy esemgangathweni.

 

I-Ceritinib ifumana Ukwamkelwa komgangatho wokuqala we-FDA kwi-ALK-Positive Lung Cancer

I-FDA iyandisile imvume ye-ceritinib. Iarhente ngoku ivunyiwe njengonyango lodidi lokuqala kwizigulana ezinesifo se-metastatic, ALK-positive, non-small-cell cell cancer. Ulawulo lwezoKutya kunye noLawulo lweeDrug (i-FDA) luyandisile ukuvunywa kwe-ceritinib. Iarhente ngoku ivunyiwe njengonyango lodidi lokuqala kwizigulana ezinesifo se-metastatic, ALK-positive, non-small-cell cell cancer (NSCLC).

I-Ceritinib (LDK378) yayivunyiwe ngaphambili kwi-2014 ye-ALK-positive metastatic NSCLC kwizigulana ezaziqhubele phambili okanye ezazinganyamezelani ne-crizotinib. Iarhente yinto ekhethiweyo ye-ALK inhibitor yomlomo, enokubakho amaxesha angama-XNUMX e-crizotinib.

Isibonakaliso esitsha sisekwe kwiziphumo zolingo lwe-ASCEND-4, iziphumo zalo zapapashwa ngoJanuwari walo nyaka eLancet. Ulingo lunezigulana ezingama-376 ezine-NSCLC ye-metastatic ene-ALK yokulungisa kwakhona i-ceritinib (i-189 yezigulana) okanye i-platinum-pemetrexed yonyango oluphindwe kabini (izigulana ezili-187).

Indawo yokugqibela yayikukusinda okuqhubela phambili, kwaye i-ceritinib yayisebenza ngakumbi. Ukuqhubeka kokuhamba ngaphandle kokuhamba phakathi kwaba ziinyanga ezili-16.6 kunye neziyobisi ezifundwayo, xa kuthelekiswa neenyanga ze-8.1 kwingalo ye-chemotherapy, ngomngcipheko we-0.55 (95% CI, 0.42-0.73; P <.0001).

Ireyithi yokuphendula iyonke ibingcono, kwi-73% nge-ceritinib kunye ne-27% nge-chemotherapy. Ixesha lokuphendula eliphakathi yayiziinyanga ezingama-23.9 nge-ceritinib kunye neenyanga ezili-11.1 ngeplatinam / pemetrexed. Okwangoku, idatha yokusinda iyonke ihlala ingenabuntu. I-Ceritinib yanikwa i-FDA, kunye nokuphononongwa okuphambili kunyango lodidi lokuqala kwesi sigulana.

Uphononongo lwe-ASCEND-4 lukwavavanye amazinga okuphendula kwizigulana ezinesilonda senkqubo ye-nervous system. Ireyithi yokuphendula ye-intracranial eqinisekisiweyo yayiyi-57% kunye ne-ceritinib, xa kuthelekiswa ne-22% kunye ne-chemotherapy.

Iziganeko ezimbi kakhulu (i-AEs) zenzeke kwi-38% yezigulana ezanyangwa nge-ceritinib, kwaye ii-AE zikhokelela ekuphelisweni kwesiyobisi kwenzeka kwi-12%. Ukuphazamiseka kwethamo ngenxa yee-AE kubonwe kwizigulana ze-ceritinib ezingama-77%, kunye ne-66% efuna ukuncitshiswa kwethamo. Ezona AE zixhaphakileyo neziyobisi kwi-ASCEND-4 zibandakanya urhudo, isicaphucaphu, ukugabha, ukudinwa, kunye nentlungu esiswini. "Ukuvunywa kwanamhlanje kubonisa inyathelo elilandelayo kuphuhliso lweZykadia njengonyango kunyango lwe-ALK-metastatic NSCLC, izisa eli nyango libalulekileyo kwisigulana apho isidingo sisekhona, utshilo u-CEO we-Novartis Oncology u-Bruno Strigini.

I-AASraw ngumenzi wobugcisa beCeritinib.

Nceda ucofe apha ngolwazi locaphulo: Unxibelelwano nathi

 

isingqiniso

[1] UMano H: I-oncogene ye-EML4-ALK: ukujolisa kumqhubi obalulekileyo ekukhuleni komhlaza wabantu. Iproc Jpn Acad Ser B yePhys Biol Sci. Ngo-2015; 91 (5): 193-201. ikhonkco: 10.2183 / pjab.91.193. [PubMed: 25971657].

[2] I-Soria JC, i-Tan DS, i-Chiari R, i-Wu YL, i-Paz-Ares L, i-Wolf J, okqhubekayo. (Matshi 2017). "Umgca wokuqala we-ceritinib xa kuthelekiswa ne-platinum-based chemotherapy kwi-ALK ehlengahlengiswe ngokutsha ngumhlaza wamaphaphu ongesosincinci (i-ASCEND-4): iilebheli ezingahleliwe, ezivulekileyo, isigaba sesi-3". ILancet. 389 (10072): 917–929.

[3] Xuan C, Gunduz V. "NSCLC MARKET - Uqikelelo lweziyobisi kwihlabathi jikelele kunye nohlalutyo lweNtengiso ukuya kwi2025". Ukuphuhliswa kweziyobisi kunye nokuhanjiswa. Hayi. Novemba-Disemba 2016.

[4] "I-FDA ivuma iCeritinib ye-ALK-Positive Lung Cancer". Ukuthintela. Epreli 29, 2014.

[5] Au TH, Cavalieri CC, Stenehjem DD Ceritinib: I-primer yoosokhemesti // Oncology ikhemesti yokuziqhelanisa. - 2017. - Umqu. 23 (8). -P. 611 (ikhonkco: 10.1177 / 1078155216672315).

[6] UNishio M, Murakami H, Horiike A, Takahashi T, Hirai F, Suenaga N, Tajima T, Tokushige K, Ishii M, Boral A, Robson M, Seto T: Isigaba I Isifundo seCeritinib (LDK378) kwizigulana zaseJapan eziPhambili, I-Anaplastic Lymphoma Kinase-Yahlengahlengiswa kwakhona yiCarcer Lung Cancer okanye ezinye iZilonda. UJ Thorac Oncol. 2015 Julayi; 10 (7): 1058-66. ikhonkco: 10.1097 / JTO.0000000000000566. [PubMed: 26020125].

[7] UGalkin AV, uMelnick JS, uKim S, uHood TL, uLi N, uLi L, uXia G, uSteensma R, uChopiuk G, uJiang J, uWan Y, uDing P, uLiu Y, uLanga F, uSchultz PG, uGrey NS, uWarmuth M Ukuchongwa kwe-NVP-TAE684, enamandla, ekhethiweyo, kunye ne-inhibitor esebenzayo ye-NPM-ALK. Iproc Natl Acad Sci US A. 2007 Jan 2; 104 (1): 270-5. Epub 2006 Dec 21. [PubMed: 17185414].

[8] UMarsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, Jiang T, Kim S, Li N, Warmuth M, Sarkisova Y, Sun F, Steffy A, Pferdekamper AC, Li AG, Joseph SB, Kim Y , Liu B, Tuntland T, Cui X, Grey NS, Steensma R, Wan Y, Jiang J, Chopiuk G, Li J, Gordon WP, Richmond W, Johnson K, Chang J, Groessl T, He YQ, Phimister A, Aycinena A, Lee CC, Bursulaya B, Karanewsky DS, Seidel HM, Harris JL, Michellys PY: Synthesis, ulwakhiwo lomsebenzi wobudlelwane, kunye nokusebenza kwe-vivo yenoveli enamandla kunye nokukhetha i-aplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (isopropylsulf onyl) phenyl) pyrimidine-2,4-diamine (LDK378) okwangoku kwisigaba 1 nakwisigaba 2 sonyango izilingo. UJ Med Chem. Ngo-2013 ngoJulayi 25; 56 (14): 5675-90. ikhonkco: 10.1021 / jm400402q. Epub 2013 Juni 26. [PubMed: 23742252].

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