特比萘芬和伊曲康唑治療甲真菌病-效果分析

特比萘芬和伊曲康唑治療甲真菌病-效果分析特比萘芬和伊曲康唑治療甲真菌病-效果分析特比萘芬和伊曲康唑治療甲真菌病-效果分析資料僅供參考文件編號：2022年4月特比萘芬和伊曲康唑治療甲真菌病-效果分析版本號：A修改號：1頁次：1.0審核：批準:發(fā)布日期：特比萘芬和伊曲康唑治療甲真菌病的成本—效果分析摘要目的：評價應用特比萘芬與伊曲康唑治療甲真菌病的經(jīng)濟效果。方法：采用循證醫(yī)學的方法自MEDLINE收集臨床資料，應用藥物經(jīng)濟學的成本-效果分析法對特比萘芬與伊曲康唑治療甲真菌病進行評價。結果：兩種藥物甲真菌病治愈率meta-分析顯示：特比萘芬（±）和伊曲康唑連續(xù)用藥（±）、沖擊療法（±），治療費用特比萘芬（￥）和伊曲康唑連續(xù)用藥（￥）、沖擊療法（￥）。結論：特比萘芬治療甲真菌病成本效果比優(yōu)于伊曲康唑。關鍵詞特比萘芬；伊曲康唑；甲真菌病；藥物經(jīng)濟學；成本-效果分析甲真菌病是指由致病性真菌侵犯甲板或甲下組織所引起的病變。常見致病菌：皮膚癬菌、酵母菌、白色念珠菌等，通常由皮膚癬菌引起的病變稱甲癬。本文我國患病率約4%~7%，以紅色毛癬菌、石膏樣毛癬菌多見。本文借助循證醫(yī)學的方法對特比萘芬和伊曲康唑治療甲真菌病的療效進行meta—分析，并進一步作兩種藥物的經(jīng)濟學評價。1材料費用計算甲真菌病為局部感染性炎癥，一般無全身癥狀，無須住院治療，特比萘芬和伊曲康唑口服吸收良好，無須特殊給藥方法，假設所有患者所進行的檢驗費用相同，為了能較好的反應藥物與療效的關系，只計算藥品直接成本。藥品價格為“2002年濟南市衛(wèi)生局藥品集中招標采購”中標零售價。特比萘芬（進口：蘭美抒，北京諾華制藥有限公司，規(guī)格：×7片，單價：￥盒；國產(chǎn)：丁克，齊魯制藥廠，規(guī)格：×6片，單價：￥盒）；伊曲康唑（進口：斯皮仁諾，西安楊森制藥有限公司，規(guī)格：×14片，單價：￥盒；國產(chǎn)：伊曲康唑膠囊，成都倍特藥業(yè)有限公司，規(guī)格：×14片，單價：￥盒）。臨床材料利用Internet網(wǎng)絡資源：MEDLINE網(wǎng)站連接（PubMed）、檢索關鍵詞：(terbinafineORitraconazole)ANDonychomycosis。納入標準：隨機對照試驗，無論是否采取盲法；試驗至少納入一平行的對照組接受安慰劑對照或藥物（特比萘芬、伊曲康唑、氟康唑、灰黃霉素）治療；使用單一特比萘芬或伊曲康唑治療無合并用藥（包括外用藥物）；治療評價應包括臨床治愈和微生物學檢查治愈。按循證醫(yī)學方法篩選臨床證據(jù)可靠性符合級別Ⅰ和級別Ⅱ文獻33篇。見表1，表2，表3。特比萘芬臨床療效優(yōu)于伊曲康唑連續(xù)用藥療法（P＞），明顯優(yōu)于伊曲康唑沖擊療法（P＜）。2成本-效果分析目前應用較普遍的治療甲真菌病口服藥物有特比萘芬、伊曲康唑、氟康唑、灰黃霉素等4種，以特比萘芬和伊曲康唑治療效果及安全性較佳[1，2，4，8，23]。成本-效果分析的目的在于平衡治療費用和效果，在其間找到一個最佳點。特比萘芬每獲得一個治療單位需￥，與伊曲康唑沖擊療法（￥）相當，遠小于伊曲康唑（￥）連續(xù)用藥。特比萘芬比伊曲康唑沖擊療法每多獲得一個治療單位需￥，小于伊曲康唑連續(xù)用藥（￥），見表4。3敏感度分析國產(chǎn)特比萘芬與進口特比萘芬無論口服制劑還是外用制劑臨床療效和安全性在統(tǒng)計學上均無顯著性差異[34，35]，國產(chǎn)伊曲康唑膠囊劑相對進口斯皮仁諾膠囊的生物利用度為%。該制劑與同類進口產(chǎn)品為等效制劑[36]。國產(chǎn)兩種藥物臨床療效和安全性與進口藥相當，但價格有一定程度下降，所以，按國產(chǎn)特比萘芬片劑、伊曲康唑膠囊劑價格進行敏感度分析。計算得表5。可見國產(chǎn)進口特比萘芬價格相差無幾，每日劑量/費用：特比萘芬進口/￥、國產(chǎn)/￥，差價￥，降幅%；伊曲康唑相差較大，連續(xù)用藥進口g/￥、國產(chǎn)g/￥，差價￥，沖擊療法進口g/￥、國產(chǎn)/￥，差價￥，降幅%。兩種藥物雖有不同程度的下降，但對分析結果沒有發(fā)生質的影響。4討論特比萘芬結構中有烯丙胺結構，能抑制真菌麥角甾醇合成過程中角鯊烯環(huán)氧化酶的作用。致使角鯊烯在真菌細胞中蓄積，破壞了真菌的膜結構，使其中主要成分如磷脂及蛋白質的合成與轉換功能明顯減退，膜功能的降低導致真菌死亡。人體細胞對本品的敏感性為真菌的萬分之一。本品有廣譜抗真菌作用，對皮膚真菌有殺菌作用，對白色念珠菌則起抑菌作用。特比萘芬通過甲床和甲母質兩條途徑向甲中進行擴散，進入指甲的藥物能以較高的濃度存在較長的時間，停藥后8周~12周甲中藥物濃度明顯高于特比萘芬對皮膚癬菌的MIC[37]。伊曲康唑是一合成廣譜抗真菌藥，為三氯唑衍生物。對皮膚癬菌、酵母菌、曲霉菌等真菌感染有效。其廣譜抗菌活性與給藥方式無關，它是通過抑制真菌細胞膜的必需成分—麥角固醇的合成而抑制真菌生長的。伊曲康唑在皮膚內(nèi)的藥代動力學比較獨特，其主要通過皮脂輸送，導致其皮膚內(nèi)濃度高于血漿內(nèi)５~１０倍，因此適于對皮膚真菌感染的治療，尤其是指（趾）甲的感染。治療開始不久就可在甲片和甲床遠端檢測到伊曲康唑，并且其保留在甲中不循環(huán)回血，直至因指甲自然生長而使其濃度降低，故無須持續(xù)給藥。特比萘芬和伊曲康唑無論治療效果還是安全性均優(yōu)于目前治療甲真菌病的其他藥物[1，2，4，8，23]，并且攜帶、應用方便。特比萘芬（治愈率：±）臨床療效優(yōu)于伊曲康唑（治愈率：連續(xù)用藥±，沖擊療法±），治療成本低于伊曲康唑連續(xù)用藥，因此可以認為特比萘芬治療甲真菌病較伊曲康唑更經(jīng)濟實惠。由于特比萘芬國產(chǎn)化比較早，幾乎與進口藥同時上市，價格較低、差價較小，每日劑量費用國產(chǎn)進口僅相差元，降幅%；伊曲康唑一直僅有進口商品占領市場，國產(chǎn)藥品2002年剛剛上市，價格較高、差價較大，每日劑量費用差價連續(xù)用藥元，沖擊療法元，降幅%，。特比萘芬每獲得一個治療單位需￥，與伊曲康唑沖擊療法（￥）相當，遠小于伊曲康唑（￥）連續(xù)用藥。特比萘芬比伊曲康唑沖擊療法每多獲得一個治療單位需￥，小于伊曲康唑連續(xù)用藥（￥）。當應用國產(chǎn)兩種藥物治療時，費用相當，特比萘芬每獲得一個治療單位需￥，伊曲康唑連續(xù)用藥（￥）沖擊療法（￥）。敏感度分析結果顯示兩種藥物降價后，對分析結果沒有發(fā)生質的影響。分析結果顯示：特比萘芬治療甲真菌病成本效果比優(yōu)于伊曲康唑。同時還可看到市場競爭的作用以及壯大國有企業(yè)的重要性。參考文獻[1]ArcaE,TastanHB,AkarA,etal.Anopen,randomized,comparativestudyoforalfluconazole,itraconazoleandterbinafinetherapyinDermatologTreat,2002,13(1):3-9[2]SaloH,PekurinenM.Costeffectivenessoforalterbinafine(Lamisil)comparedwithoralfluconazole(Diflucan)inthetreatmentofpatientswithtoenailonychomycosis.Pharmacoeconomics,2002,20(5):319-324[3]SigurgeirssonB,OlafssonJH,SteinssonJB,etal.Long-termeffectivenessoftreatmentwithterbinafinevsitraconazoleinonychomycosis:a5-yearblindedprospectivefollow-upstudy.ArchDermatol,2002,138(3):353-357[4]GuptaAK,Gregurek-NovakT.Efficacyofitraconazole,terbinafine,fluconazole,griseofulvinandketoconazoleinthetreatmentofScopulariopsisbrevicauliscausingonychomycosisofthetoes.Dermatology,2001,202(3):235-238[5]GuptaAK,LyndeCW,KonnikovN.Single-blind,randomized,prospectivestudyofsequentialitraconazoleandterbinafinepulsecomparedwithterbinafinepulseforthetreatmentoftoenailAmAcadDermatol,2001,44(3):485-491[6]GuptaAK,KonnikovN,LyndeCW.Single-blind,randomized,prospectivestudyonterbinafineanditraconazolefortreatmentofdermatophytetoenailonychomycosisintheAmAcadDermatol,2001,44(3):479-484[7]SigurgeirssonB,BillsteinS,RantanenT,etal.Study:efficacyandtolerabilityofcontinuousterbinafine(Lamisil)comparedtointermittentitraconazoleinthetreatmentoftoenailonychomycosis.Lamisilvs.ItraconazoleinOnychomycosis.BrJDermatol,1999,141(Suppl56):5-14[8]HavuV,HeikkilaH,KuokkanenK,etal.Adouble-blind,randomizedstudytocomparetheefficacyandsafetyofterbinafine(Lamisil)withfluconazole(Diflucan)inthetreatmentofonychomycosis.BrJDermatol,2000,142(1):97-102[9]KejdaJ.ItraconazolepulsetherapyvscontinuousterbinafinedosingfortoenailMed,1999,SpecNo:12-15[10]DegreefH,delPalacioA,MygindS,etal.Randomizeddouble-blindcomparisonofshort-termitraconazoleandterbinafinetherapyfortoenailonychomycosis.ActaDermVenereol,1999,79(3):221-223[11]EvansEG,SigurgeirssonB.Doubleblind,randomisedstudyofcontinuousterbinafinecomparedwithintermittentitraconazoleintreatmentoftoenailonychomycosis.BMJ,1999,318(7190):1031-1035[12]DrakeLA,ShearNH,ArletteJP,etal.Oralterbinafineinthetreatmentoftoenailonychomycosis:NorthAmericanmulticentertrial.JAmAcadDerm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Table1Studiesusedinthemata-analysistocalculatecureratewhenterbinafineisusedtotreatonychomycosisAutherTypeofStudyDosage(mg/d)ncCurerate(%)ArcaE[1]Open,randomized,comparative2501610SaloH[2]Double-blind,randomized,comparative2504832SigurgeirssonB[3]Double-blind,randomized,comparative2507434GuptaSingle-blind,randomized,comparative2501211GuptaSingle-blind,randomized,comparative2509029Gupta Single-blind,randomized,comparative2505031SigurgeirssonB[7]Double-blind,randomized,comparative25010781HavuV[8]Double-blind,randomized,placebo-controlled2504641KejdaJ[9]Open,randomized,comparative250162123DegreefH[10]Double-blind,randomized,comparative25014698EvansEG[11]Double-blind,randomized,comparative25010781DrakeLA[12]Double-blind,randomized,placebo-controlled250358265TauschI[13]Double-blind,randomized,comparative2507655EllisDH[14]Double-blind,randomized,placebo-controlled25011842AlpsoyE[15]Open,randomized,comparative2502419TostiA[16]Open,randomized,comparative2501716DeBackerM[17]Double-blind,randomized,comparative250163119WatsonA[18]Double-blind,randomized,comparative2505649BrautigamM[19]Double-blind,randomized,comparative2508670FaergemannJ[20]Double-blind,randomized,comparative2504336ArenasR[21]Open,randomized,comparative2501717GoodfieldMJ[22]Double-blind,randomized,comparative2504537vanderSchroeffJG[23]Double-blind,randomized,comparative2503424SavinRC[24]Double-blind,randomized,comparative2501612Table2Studiesusedinthemata-analysistocalculatecureratewhenitraconazoleisusedtotreatonychomycosisAutherTypeofStudyDosage(mg/d)ncCurerate(%)ArcaE[1]Open,randomized,comparative2001811GuptaSingle-blind,randomized,comparative2001212GuptaSingle-blind,randomized,comparative2007539GuptaSingle-blind,randomized,comparative2005131DegreefH[10]Double-blind,randomized,comparative20014689WatsonA[18]Double-blind,randomized,comparative20077186BrautigamM[19]Double-blind,randomized,comparative2008453ArenasR[21]Open,randomized,comparative2002322LechaM[25]Open,randomized,comparative2003222ElewskiBE[26]Double-blind,randomized,comparative20010959HanekeE[27]randomized,comparative200188147HanekeE[28]Double-blind,randomized,comparative200540400HavuV[29]Double-blind,randomized,comparative2006241HoneymanJF[30]Double-blind,randomized,comparative2008371JonesHE[31]Double-blind,randomized,placebo-controlled2003524OdomR[32]Double-blind,randomized,placebo-controlled2003818USproductmonopraph[33]Double-blind,randomized,placebo-controlled20011059SigurgeirssonB[3]Double-blind,randomized,comparative4007710SigurgeirssonB[7]Double-blind,randomized,comparative40010741KejdaJ[9]Open,randomized,comparative400153115EvansEG[11]Double-blind,randomized,comparative40010741TostiA[16]Open,randomized,comparative4002015HavuV[28]Double-blind,randomized,comparative4005941Tab3RanksumtestofitraconazoleandterbinafineinonychomycosisGroupRanksumofdifferenceαSRA－RBqP1and33＜1and242＞2and32＜DrugRegimenCost（C）Curerate（E，%）95%confidenceintervalC/EΔC/ΔEterbinafine250mg/d×12weeks±~itraconazole200mg/d×12weeks±~200mgweek×3pulses±~—Tab4Cost-effectivenessanalysis(￥)Tab5Analysisofsemsitivities(￥)DrugRegimenCost（C）Curerate（E，%）C/EΔC/ΔEterbinafine250mg/d×12weeks± itraconazole200mg/d×12weeks±200mgweek×3pulses±