| 词条 | Lumacaftor/ivacaftor |
| 释义 |
| image = Ivacaftor and lumacaftor.svg | width = 240 | type = combo | component1 = Lumacaftor | class1 = CFTR chaperone | component2 = Ivacaftor | class2 = CFTR potentiator | tradename = Orkambi | Drugs.com = {{Drugs.com|monograph|orkambi}} | MedlinePlus = | pregnancy_AU = | pregnancy_US = B | pregnancy_US_comment = [1] | pregnancy_category= | licence_EU = yes | legal_AU = | legal_CA = | legal_UK = POM | legal_US = Rx-only | legal_UN = | legal_NZ = | legal_status = | routes_of_administration = By mouth | CAS_number = | ATCvet = | ATC_prefix = R07 | ATC_suffix = AX30 | PubChem = | DrugBank = | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D10685 }}Lumacaftor/ivacaftor, sold under the brand name Orkambi, is a combination of lumacaftor and ivacaftor used to treat people with cystic fibrosis who have two copies of the F508del mutation.[1] It is unclear if it is useful in cystic fibrosis due to other causes.[1] It is taken by mouth.[1] Common side effects include shortness of breath, nausea, diarrhea, feeling tired, hearing problems, and rash.[1][2] Severe side effects may include liver problems and cataracts.[1] Ivacaftor increases the activity of the CFTR protein, while lumacaftor improves protein folding of the CFTR protein.[1][9] It was approved for medical use in the United States in 2015 and in Canada in 2016.[1][3] In the United Kingdom the medication costs the NHS more than £4,000 a month as of 2018.[2] In the United States it costs more than $US 22,000 a month as of 2018.[4][5] Its use is not recommended in the United Kingdom as of 2018.[2] Medical useThe combination of lumacaftor/ivacaftor is used to treat people with cystic fibrosis who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein that causes the disease.[6][17] This genetic abnormality is present in about half of cystic fibrosis cases in Canada.[3] Its use is not recommended for anyone with cystic fibrosis in the United Kingdom as of 2018.[2] While the medication resulted in improvement to FEV1, the improvement seen did not reach clinical significance.[3] The medication also does not appear to change a person's quality of life or the number of times per year a person experiences a deterioration of lung function.[3] Effects on life expectancy are unclear.[3] Side effectsSome people taking the combination drug had elevated transaminases; the combination drug should be used with caution for people with advanced liver disease and liver function should be measured for the first three months for all people starting the combination drug.[6] People starting the combination have respiratory discomfort, and some children taking the combination drug developed cataracts.[6] Lumacaftor/ivacaftor may interfere with hormonal contraceptives. Dosage of the combination drug should be reduced if the person is taking a drug that inhibits CYP3A, and inducers of CYP3A should not be used concomitantly.[6] Mechanism of actionF508del is a mutation that causes the CFTR protein to misfold and cells destroy such proteins soon after they are made; lumacaftor acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface.[7][8] Ivacaftor is a potentiator of CFTR that is already at the cell surface, increasing the probability that the defective channel will be open and allow chloride ions to pass through the channel pore.[9] The two drugs have synergistic effects.[9] Physical propertiesEach of lumacaftor and ivacaftor is a white to off-white powder that is practically insoluble in water. The combination drug is a single pill containing 200 mg of lumacaftor and 125 mg of ivacaftor.[6] HistoryLumacaftor/ivacaftor was approved by the FDA in July 2015 under breakthrough therapy status and under a priority review.[10] Previously approved for adults and pre-teens, approved on 8-7-18 for children age 2–5.{{fact|date=February 2019}} Society and cultureAs of March 2016 the combination drug cost $259,000 a year in the United States.[11] In Denmark, it was estimated in August 2015 that if the drug were introduced, the cost would amount to 2 million Danish krones (approximately 270,000 euro) each year per person.[12] The Dutch Minister of Health announced in October 2017 that the drug would not be admitted to the public health insurance package, making it impossible to have treatment with the drug covered by Dutch health insurance. The minister stated that the price for the drug, negotiated to 170,000 euro per patient per year, is "unacceptably high in relation to the relatively modest effect, as determined by the (Dutch) Healthcare Institute". Approximately 750 patients are affected by this decision.[13] On 25 October, the Dutch Minister of Health announced that an agreement had been brokered with Vertex Pharmaceuticals, the company that manufactures the drug, resulting in admittance to the Dutch public health insurance package. Part of the agreement is that the end result of the negotiation about the price of the treatment will not be disclosed.[14] References1. ^1 2 3 4 5 6 {{cite web |title=Orkambi Monograph for Professionals |url=https://www.drugs.com/monograph/orkambi.html |website=Drugs.com |publisher=AHFS |accessdate=8 January 2019 |language=en}} {{Other respiratory system products}}2. ^1 2 3 {{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=293–294|edition=76|url=https://bnf.nice.org.uk/drug/lumacaftor-with-ivacaftor.html}} 3. ^1 2 3 4 5 {{cite web |title=[116] New drug for cystic fibrosis: Regulatory approval, clinical uncertainty? |url=https://www.ti.ubc.ca/2018/12/27/116-new-drug-for-cystic-fibrosis-regulatory-approval-clinical-uncertainty/ |website=Therapeutics Initiative |publisher=Therapeutics Initiative |accessdate=8 January 2019 |language=en-CA |date=28 December 2018}} 4. ^{{cite journal |last1=Ferkol |first1=T |last2=Quinton |first2=P |title=Precision Medicine: At What Price? |journal=American Journal of Respiratory and Critical Care Medicine |date=15 September 2015 |volume=192 |issue=6 |pages=658–9 |doi=10.1164/rccm.201507-1428ED |pmid=26207804}} 5. ^{{cite news |last1=Thomas |first1=Katie |title=A Drug Costs $272,000 a Year. Not So Fast, Says New York State. |url=https://www.nytimes.com/2018/06/24/health/drug-prices-orkambi-new-york.html |accessdate=8 January 2019 |work=The New York Times |date=24 June 2018}} 6. ^1 2 3 4 5 {{cite web |title=Orkambi |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206038Orig1s000lbl.pdf |website=www.accessdata.fda.gov |accessdate=8 January 2019 |date=2015}} 7. ^{{cite web|title=Orkambi (lumacaftor and ivacaftor)|url=http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100082/orkambi-lumacaftor-and-ivacaftor|publisher=CenterWatch|accessdate=24 March 2016}} 8. ^{{cite journal|last1=Ren|first1=H. Y.|last2=Grove|first2=D. E.|last3=De La Rosa|first3=O.|last4=Houck|first4=S. A.|last5=Sopha|first5=P.|last6=van Goor|first6=F.|last7=Hoffman|first7=B. J.|last8=Cyr|first8=D. M.|title=VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1|journal=Molecular Biology of the Cell|date=7 August 2013|volume=24|issue=19|pages=3016–3024|doi=10.1091/mbc.E13-05-0240|pmid=23924900|pmc=3784376}} 9. ^1 2 {{cite journal | pmid = 26416827 | doi=10.1177/1753465815601934 | volume=9 | issue=6 | title=Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects | year=2015 | journal=Ther Adv Respir Dis | pages=313–26 | last1 = Kuk | first1 = K | last2 = Taylor-Cousar | first2 = JL}} 10. ^{{cite web|title=FDA approves new treatment for cystic fibrosis|url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm453565.htm|publisher=United States Food and Drug Administration|date=July 2, 2015}} 11. ^{{cite web|last1=Wasserman|first1=Emily|title=NICE gives initial thumbs-down to Vertex's CF combo med Orkambi, citing costs|url=http://www.fiercepharma.com/story/nice-gives-initial-thumbs-down-vertexs-cf-combo-med-orkambi-citing-costs/2016-03-23|publisher=FiercePharma|date=March 23, 2016}} 12. ^{{Cite news | author = Sebastian Stryhn Kjeldtoft | title = 10-årige Elisabeth spiser 33 piller om dagen | publisher = Information | date = 1 August 2015 | url = http://www.information.dk/540825 | language = Danish}} 13. ^{{Cite news | author = | title = Onderhandelingen over taaislijmziekte weer mislukt | trans-title= Negotiations over throat gland disease failed again | publisher = NOS | date = 9 August 2017 | url = https://nos.nl/artikel/2197100-onderhandelingen-over-taaislijmziekte-weer-mislukt.html | language = Dutch | agency = Algemeen Nederlands Persbureau}} 14. ^{{Cite news | author = R. Zenthis | title = Medicijn tegen taaislijmziekte toch opgenomen in basispakket | trans-title= Cystic Fibrosis medicine approved for basic insurance package | publisher = Nu.nl | date = 25 August 2017 | url = https://www.nu.nl/gezondheid/4979288/medicijn-taaislijmziekte-toch-opgenomen-in-basispakket.html | language = Dutch | agency = Algemeen Nederlands Persbureau/Nu.nl}} 4 : Combination drugs|Cystic fibrosis|Breakthrough therapy|RTT |
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