Anti-Cancer Drugs Acalabrutinib: Ọgwụgwọ Maka CLL / SLL / MCL - AASraw
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Ọgwụ na-egbochi Ọrịa Cancer Acalabrutinib

 

  1. Akalabrutinib Backgroud
  2. Nyocha Acalabrutinib
  3. Ọgwụgwọ Acalabrutinib (Eji ya maka)
  4. Acalabrutinib usoro nke Action
  5. Kedu ihe mmetụta dị egwu nke Acalabrutinib?
  6. Akalabrutinib VS Ibrutinib
  7. Nnyocha: Acalabrutinib On Na-agwọ Ọrịa lymphocytic na-adịghị ala ala (CLL)

 

Akalabrutinib Backgroud

Ruo ugbu a, acalabrutinib ejirila na ọnwụnwa na-amụ banyere ọgwụgwọ B-All, Myelofibrosis, Ovarian Cancer, Multiple Myeloma, na Hodgkin Lymphoma, n'etiti ndị ọzọ.

N'ihe dị ka Ọktọba 31, 2017 FDA kwadoro Calquence ọnụ (acalabrutinib) nke Astra Zeneca. Onye na-eme ihe a Bruton Tyrosine Kinase (BTK) gosipụtara maka ọgwụgwọ ọrịa leukemia lymphocytic na-adịghị ala ala, obere lymphocytic lymphoma, yana ndị ọrịa toro eto nwere Mantle Cell Lymphoma (MCL) ndị natarala opekata mpe otu usoro ọgwụgwọ.

A makwaara dị ka AKP-196, acalabrutinib a na-ewerekwa ọgbọ nke abụọ BTK inhibitor n'ihi na ọ bụ n'echepụtara ya ka ọ dị ike ma họrọ karịa ibrutinib, na-atụ anya na ọ ga-egosiputa obere mmetụta ọ bụla n'ihi na ọ belatara mmetụta ndị na-ahụ anya na ebumnuche ndị ọzọ karịa BTK.

Ka o sina dị, acalabrutinib ka a kwadoro n'okpuru ụzọ nkwado ngwa ngwa nke FDA, nke dabere na ngụkọta nzaghachi zuru oke ma kwalite nkwenye mbụ nke ọgwụ ndị na-emeso ọnọdụ siri ike ma ọ bụ / yana mejupụta mkpa ahụike na-enweghị isi dabere na njedebe njedebe. Approvalga n'ihu nkwado maka akara aka nnabata acalabrutinib nwere ike bụrụ ihe dabere na nyocha na-aga n'ihu yana nkọwa nke uru ahụike na ọnwụnwa nkwupụta.

Ọzọkwa, FDA nyere ọgwụ a Ihe Nleba Anya na Breakthrough Therapy designations. Ọ natara aha Ọrịa Orphan, nke na-enye mkpali iji nyere aka na ịgba ume mmepe ọgwụ maka ọrịa ndị na-adịghị ahụkebe. N'oge a, ihe karịrị ule nyocha 35 gafere mba 40 nwere ihe karịrị ndị ọrịa 2500 na-aga n'ihu ma ọ bụ emechaa maka ịmatakwu nyocha maka nghọta ka mma na ịgbasa usoro ọgwụgwọ nke acalabrutinib 5.

 

Akalabrutinib Nyocha

Acalabrutinib (CAS: Ekwereghi1420477-60-6), nke a na-ere ahịa n'okpuru aha nke Calquence® na US na Canada, bụ onye na-egbochi obere mkpụrụ ndụ nke abụọ nke Bruton's tyrosine kinase (BTK). N'elu nchịkwa ọnụ, acalabrutinib na-ejide ma na-egbochi ọrụ nke BTK nke na-egbochi ma B-cell ọrụ na B-cell-mediated signaling. Omume a na - eduga na mgbochi nke mkpụrụ ndụ B na - adịghị mma nke na - egosi BTK. Achọrọ BTK maka akara ngosi B-cell, na-arụ ọrụ dị mkpa na ngụkọta B-cell, ma gosipụta ya n'ọtụtụ ọnụọgụ B-cell, gụnyere CLL / SLL. Okwu BTK na sel etuto na-emetụta ụba na nlanarị. Dị ka onye na-emechi BTK nke abụọ, e mepụtara acalabrutinib iji bulie mmetụta na BTK ma belata ọrụ ebumnuche na TEC (Tec Protein Tyrosine Kinase), EGFR (epidermal growth factor receptor), na ITK (interleukin-2-inducible T- cell kinase). Ọgbọ mbu BTK inhibitor, ibrutinib (Imbruvica), enweghi nkọwa a nke na - ebute nsogbu dị njọ. Na mgbakwunye na CLL / SLL, acalabrutinib ka a kwadoro maka Mantle Cell Lymphoma (MCL). National Cancer Center Network (NCCN) Ntuziaka depụtara acalabrutinib na ma ọ bụ na-enweghị obinituzumab dị ka usoro ọgwụgwọ mbụ maka CLL / SLL yana nke dabara adaba maka ojiji na nlọghachi ma ọ bụ na-agbagha (R / R) CLL.

 

Akalabrutinib Ọgwụgwọ (Ejiri maka)

Acalabrutinib a na-eji na-emeso ndị mmadụ na mantle cell lymphoma (MCL; a-eto ngwa ngwa cancer na-amalite na mkpụrụ ndụ nke dịghịzi usoro) bụ ndị na-ama na-emeso dịkarịa ala otu ọzọ ọgwụ ọgwụ.

Acalabrutinib na-eji naanị ma ọ bụ na obinutuzumab (Gazyva) iji na-emeso leukemia na-adịghị ala ala (CLL; ụdị cancer nke na-amalite na sel ọbara ọcha) na obere lymphocytic lymphoma (SLL: ụdị nke cancer nke na-amalite na sel ọbara ọcha).

Acalabrutinib nọ na klas nke ọgwụ a na-akpọ ndị na-emechi kinase. Ọ na - arụ ọrụ site na igbochi ọrụ nke protein na - adịghị mma nke na - egosi mkpụrụ ndụ cancer ịba ụba. Nke a na - enyere aka ịkwụsị mgbasa nke mkpụrụ ndụ kansa.

 

Akalabrutinib usoro Of Action

Mantle Cell Lymphoma (MCL) bụ ụdị obere B-cell na-abụghị Hodgkin lymphoma (NHL) nke nwere obere amụma. N'ikpeazụ, nlọghachi azụ bụ ihe nkịtị na ndị ọrịa MCL ma n'ikpeazụ na-anọchite anya Ọrịa.

Lymphoma na-eme mgbe lymphocytes na-alụso ọrịa ọgụ na-eto ma na-amụba n'enweghị nchịkwa. Lydị lymphocytes ndị ahụ nwere ike ịga ọtụtụ akụkụ ahụ, gụnyere mkpụrụ lymph, splin, ụmị ọkpụkpụ, ọbara, na akụkụ ndị ọzọ ebe ha nwere ike ịmụba ma mepụta oke (es) akpọrọ akpụ. Otu n'ime ụdị lymphocytes ndị bụ isi nke nwere ike ịmalite lymfomas nwere ọrịa bụ B-lymphocytes (B-cells) nke ahụ.

Bruton Tyrosine Kinase (BTK) bụ akara ngosi nke B-cell antigen receptor na ụzọ nnabata cytokine. Suchdị BTK dị otú ahụ na-ebute mmalite nke ụzọ dị mkpa maka mmụba B-cell, ahia ahia, chemotaxis, na adhesion.

Acalabrutinib bụ obere mkpụrụ ndụ na-egbochi BTK. Ma acalabrutinib na metabolite na-arụ ọrụ, ACP-5862, na-arụ ọrụ iji mepụta njikọ nke coystlent (Cys481) na saịtị BTK, na-eduga na igbochi ọrụ BTK enzymatic. na-egosi protein na-egosi CD86 na CD69, nke n'ikpeazụ na-egbochi mmụba B-cell na-adịghị mma.

Ọ bụ ezie na a na-ahụkarị ibrutinib dị ka onye izizi BTK mbụ, acalabrutinib ka a na-ewere dị ka ọgbọ BTK nke abụọ n'ihi na ọ na-egosipụta nhọrọ dị elu na mgbochi nke ọrụ ezubere iche nke BTK ebe ọ nwere nnukwu IC50 ma ọ bụ n'ụzọ ọzọ enweghị ihe mgbochi na ọrụ kinase nke ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, na YES1.

Dị ka a pụrụ isi kwuo ya, acalabrutinib ka e mere n'echeghị echiche ka ọ dị ike ma họrọ karịa ibrutinib, n'oge niile na-egosiputa obere mmetụta na - adịghị mma - na tiori - n'ihi ọgwụ belata ọgwụ ọ na - ebute

 

Kedu ihe mmetụta dị egwu nke Acalabrutinib?

Acalabrutinib nwere ike ịkpata nnukwu nsogbu, gụnyere:

Ọrịa siri ike nwere ike ime n'oge ọgwụgwọ Acalabrutinib ma nwee ike ịnwụ. Onye na-ahụ maka ahụike gị nwere ike ikwu ụfọdụ ọgwụ ma ọ bụrụ na ịnwekwu ihe egwu ị bute ọrịa. Gwa onye na-ahụ maka ahụike gị ozugbo ọ bụrụ na ị nwere akara ma ọ bụ ihe mgbaàmà ọ bụla nke ọrịa, gụnyere ahụ ọkụ, akpata oyi, ma ọ bụ ihe mgbaàmà.

Nsogbu ọgbụgba (ọgbụgba) nwere ike ime n'oge ọgwụgwọ na Acalabrutinib ma nwee ike dị njọ ma nwee ike iduga ọnwụ. Ihe ize ndụ gị nke ọbara ọgbụgba nwere ike ịba ụba ma ọ bụrụ na ị na-a medicineụkwa ọgwụ na-ebelata ọbara. Gwa onye na-elekọta ahụike gị ma ọ bụrụ n’inwe ihe ịrịba ama ma ọ bụ ihe mgbaàmà ọ bụla nke ọbara ọgbụgba, gụnyere ọbara dị na oche gị ma ọ bụ stool ojii (ọ dị ka tar), mmamịrị pink ma ọ bụ nchara nchara, ọbara ọgbụgba na-atụghị anya ya ma ọ bụ ọbara ọgbụgba nke siri ike ma ọ bụ na ịnweghị ike ịchịkwa, ịgbọ agbọ ọbara ma ọ bụ ịgbọ agbọ na ọ dị ka kọfị kọfị, kpochie ọbara ma ọ bụ mkpụkọ ọbara, nju anya, adịghị ike, mgbagwoju anya, mgbanwe n'okwu gị, isi ọwụwa nke na-adịte aka, ma ọ bụ mmerụ ahụ ma ọ bụ ọbara ọbara

Mbelata nke ọnụọgụ ọbara. Mbelata nke ọbara (mkpụrụ ndụ ọbara ọcha, platelet, na mkpụrụ ndụ ọbara uhie) na-adịkarị na Acalabrutinib, mana ọ dịkwa ike. Onye na-ahụ maka ahụike gị kwesịrị ime nyocha ọbara ka ịlele ọbara gị oge niile n'oge ọgwụgwọ na Acalabrutinib.

Ọrịa cancer nke abụọ. Ọrịa ọhụrụ emeela na ndị mmadụ n'oge ọgwụgwọ Acalabrutinib, gụnyere ọrịa kansa nke anụ ahụ ma ọ bụ akụkụ ndị ọzọ. Onye nlekọta ahụike gị ga-enyocha gị maka ọrịa kansa anụ ahụ n'oge ọgwụgwọ na Acalabrutinib. Jiri mkpuchi anwụ mgbe ịnọ n'èzí na ìhè anyanwụ.

Nsogbu obi obi (atrial fibrillation na atrial flutter) emeela na ndị a na-emeso Acalabrutinib. Gwa onye na-ahụ maka ahụike gị ma ọ bụrụ na ị nwere nke ọ bụla n’ime ihe ịrịba ama ma ọ bụ ihe mgbaàmà ndị a: ngwa ngwa ma ọ bụ na-adịghị agbanwe agbanwe obi, uju, inwe nkụda mmụọ, obi erughị ala, ma ọ bụ iku ume.

Mmetụta kachasị emetụta Acalabrutinib gụnyere isi ọwụwa, afọ ọsịsa, mọzụlụ na nkwonkwo mgbu, ọrịa iku ume iku ume nke elu, na ọnya.

Ihe ndị a abụghị mmetụta mmetụta niile nke Acalabrutinib. Kpọọ dọkịta gị maka ndụmọdụ ahụike gbasara mmetụta ndị ọzọ. Nwere ike ịkọ akụkọ gbasara FDA na 1-800-FDA-1088.

 

Akalabrutinib

 

 

Akalabrutinib VS Ibrutinib

BTK na-ekere òkè dị mkpa n'ụzọ mgbaàmà nnabata B-cell; acalabrutinib kegidere BTK enweghi ike igbochi ya ma gbochie ọrụ ya. Emere ọgwụ ahụ dị ka onye nwere ike ịhọrọ BTK na-egbochi ya, iji gbalịa iwelata ụfọdụ ọgwụ ndị na-egbochi ọgwụ ndị a na-ahụkarị. ibrutinib. Dị ka Dr. Brown si kwuo, "Acalabrutinib bụ onye na-egbochi BTK ịhọrọ ndị nwere nsogbu ọria, ọkachasị ihe gbasara obi."

Ihe omuma data yiri ihe di n'etiti acalabrutinib na ibrutinib, obu ezie na ntughari bu ogologo oge na ibrutinib, Dr. Brown gara n'ihu. Ya mere, ọdịiche dị n'etiti ọgwụ ndị ahụ dị na profaịlụ mmetụta-akụkụ ha. Ibrutinib na-anabataghị ihe ọ bụla na ndị ọrịa meworo agadi ma jikọta ya na ọnụ ọgụgụ dị elu nke atr fibrillation na ọbara mgbali elu. “Acalabrutinib dị mma karịa [karịa ibrutinib], yabụ ana m eji ya eme ihe ọkachasị, ọkachasị ndị ọrịa m toro eto,” ka o kwuru.

Nkwado ọgwụ na CLL, nke enyere na November 2019, dabere na nchekwa na nrụpụta ọrụ sitere na nyocha nwa oge nke ikpe ELEVATE-TN nke ndị ọrịa nwere CLL na-agabatabeghị na ikpe ASCEND nke ndị ọrịa nwere CLL na-alaghachi azụ ma ọ bụ na-agbagha. gosiputara nlanarị nke enweghị ọganihu ma e jiri ya tụnyere usoro ọgwụgwọ, yana profaịlụ ngwangwa dị mma. Na ikpe ELEVATE-TN, kpọmkwem, acalabrutinib tinyere obinutuzumab yana monotherapy belata ihe ize ndụ nke ọrịa ọrịa ma ọ bụ ọnwụ site na 90% na 80%, n'otu n'otu.

"Ndidi na-anọgide na-abụ nsogbu na ọnọdụ ọgwụgwọ ugbu a nke CLL, nke nwere ike ịchọ ọgwụgwọ na-aga n'ihu ruo ọtụtụ afọ," ka Jeff Sharman, MD, Director of Research na Willamette Valley kwuru cancer Institute, Director Medical nke Hematology Research maka US Oncology Network, na onye ndu edemede nke ikpe ELEVATE-TN, na nkwupụta mgbasa ozi. "Na ọnwụnwa ELEVATE-TN na ASCEND na-atụnyere [acalabrutinib] na usoro ọgwụgwọ ndị a na-ejikarị eme ihe, [acalabrutinib] gosipụtara mmụba bara uru nke ahụike na nlanarị na-enweghị ọganihu na ndị ọrịa n'ofe ọtụtụ ntọala, ma na-ejigide nnabata ya na profaịlụ nchekwa."

 

Nnyocha: Akalabrutinib Na-emeso Ọrịa ịba ọcha na-adịghị ala ala (CLL)  

(1) Ọrịa ịba ọcha na-adịghị ala ala (CLL)

Ọrịa leukemia na-ala ala (CLL), nke kachasị okenye na-arịa ọrịa leukemia, bụ neoplasm nke na-agụnye monomorphic obere mkpụrụ ndụ B tozuru etozu nke na-emekọ ọnụ CD5 na CD23. Ọnọdụ ọgwụgwọ nke CLL agbanweela n'ụzọ dị egwu n'afọ ndị na-adịbeghị anya. Ọgwụ ndị na-elekwasị anya na ndị na-edozi na ụzọ B cell antigen receptor (BCR), dị ka ibrutinib, egosiputa mmụba na ọganihu n'efu na nlanarị zuru oke, gụnyere ndị ọrịa nwere nnukwu ọrịa. Ọ bụ ezie na ọgwụ ndị a agbanweela usoro ọgwụgwọ na ndị ọrịa nwere CLL, ikpughe ọgwụgwọ na ike na ibrutinib nwere ike ịbelata n'ihi profaịlụ mmetụta na ọgwụgwọ metụtara ọrịa. Acalabrutinib, ọgbọ nke abụọ na onye na-ahọpụta onye na-emechi Bruton's tyrosine kinase (BTK) onye mepụtara, ka emepụtara iji bulie nrụpụta ọrụ ka ọ na-ebelata ihe omume ọjọọ metụtara ibrutinib bụ nke e chere na ọ bụ nke abụọ maka mbibi-ibrutinib. Nyocha a ga-achikota mmepe, nyocha nke ụlọ ọgwụ, na nnwale nnwale dị mkpa nke gosipụtara nrụpụta acalabrutinib na profaịlụ na-egbu egbu na CLL.

 

(2) Nnyocha ọmụmụ nke Acalabrutinib na CLL

Ọtụtụ nchọpụta doro anya gosipụtara nrụpụta ọrụ nke acalabrutinib na mgbochi BTK. Mgbe a nwalere ya na ọbara mmadụ niile, acalabrutinib nwere mgbochi BTK ma e jiri ya tụnyere ibrutinib. Achọpụtara Ibrutinib na-akpata apoptosis na-abawanye nke sel CLL ma e jiri ya tụnyere acalabrutinib, nke enwere ike ịkọwapụta site na mmetụta ebumnuche nke ibrutinib. Acalabrutinib enwechaghị mmetụta na mkpụrụ ndụ T nke dị mma nwere ike ịbụ n'ihi nhọta ya ma ọ bụrụ na e jiri ya tụnyere ibrutinib.

A na-enyocha mmetụta mgbochi nke acalabrutinib na ụdị abụọ CLL na-egbu egbu: usoro nnabata nnabata TCL1 na ụdị CLL nke xenografted. E gosipụtara Acalabrutinib iji gbochie akara BCR na ọgwụgwọ na acalabrutinib jikọtara ọnụ ọgụgụ dị ukwuu na nlanarị ma e jiri ya tụnyere ụmụ oke na-adịghị edozi (median 81 days vs 59 days, p = 0.02). Acalabrutinib mekwara ka mbelata dị ukwuu na mkpụrụ ndụ na-aba ụba na oke mkpụmkpụ akpụ na splin.

Enyochala mmekọrịta Acalabrutinib na mgbochi CD20 monoclonal na-alụso ọrịa ọgụ ọgụ. Ibrutinib nwere ike igbochi ọtụtụ usoro nke usoro mgbochi CD20 na-egbochi kpọmkwem cytotoxicity cellular na phagocytosis nke nwere ike ibelata mmetụta mgbochi akpụ ha. ma chọpụta na ọ naghị egbochi usoro ndị a, ikekwe n'ihi ntakịrị ntakịrị mmetụta nke acalabrutinib.Ọ bụ ezie na ngwakọta nke acalabrutinib na mgbochi CD20 monoclonal antibody amụbeghị na ụdị vivo, ọtụtụ usoro 2 na nkebi Ihe omumu 3 na-aga n’ihu ma ọ bụ emechaala nke gosipụtara nrụpụta ọrụ acalabrutinib yana njikọta anti-CD20 monoclonal antibody.

A na-amụrụ ihe ndị ọzọ acalabrutinib na in vitro na vivo. Acalabrutinib jikọtara ya na PI3Kdelta inhibitor (ACP-319) na ihe atụ CLL murine ma gosipụta mbelata dị ukwuu na mmụba tumo, NF-KB na ngosipụta nke BCL-xL na MCL-1 ma e jiri ya tụnyere monotherapy. adịghị edebanye aha na usoro ikpe na-agwọ ọrịa na acalabrutinib na venetoclax. Nnwale a na-esote na ndụ vivo gosipụtara ogologo oge na ụmụ oke na-emeso ma acalabrutinib na venetoclax ma e jiri ya tụnyere ọgwụ ọ bụla.

 

(3) Mkpebi

Na nchịkọta, ọmụmụ ihe ndị akọwapụtara na-egosi na acalabrutinib nwere nnukwu nrụpụta ọrụ na ọgwụgwọ nke CLL, ma ọgwụgwọ adịghị mma ma weghachite ntughari. O doro anya ma nrụpụta ọrụ ahụ hà nhata ma ọ bụ karịa ibrutinib na ọmụmụ ihe na-aga n'ihu na mbọ iji tụnyere ndị ọrụ ndị a. Ọ bụ ezie na nsị metụtara BTK dị ka ọbara ọgbụgba ma ọ bụ ihe omume fibrillation nke atrial bụ ihe ndị na-adịghị adịkarị, acalabrutinib nwere profaịlụ AE pụrụ iche, ọkachasị isi ọwụwa, nke chọrọ nlezianya nlezianya na nka na njikwa. Data sitere n'ọmụmụ ihe na-aga n'ihu na-enyocha njikọta na acalabrutinib ga-enyere aka ịkọwawanye ọrụ ya na njikwa nke CLL. N'ikpeazụ, site na nkwado FDA, ahụmịhe nke ụwa na acalabrutinib ga-enyere aka ịkọwapụta profaịlụ nsị.

 

Reference

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