1、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(píng)價(jià)應(yīng)用特比萘芬與伊曲康唑治療甲真菌病的經(jīng)濟(jì)效果。方法：采用循證醫(yī)學(xué)的方法自MEDLINE收集臨床資料，應(yīng)用藥物經(jīng)濟(jì)學(xué)的成本-效果分析法對(duì)特比萘芬與伊曲康唑治療甲真菌病進(jìn)行評(píng)價(jià)。結(jié)果：兩種藥物甲真菌病治愈率meta-分析顯示：特比萘芬（73.0516.73）和伊曲康唑連續(xù)用藥（66.8915.82）、沖擊療法（47.9625.56），治療費(fèi)用特比萘芬（￥1420.80）和伊曲康唑連續(xù)用藥（￥1731.6）、沖擊療法（￥865.80）。結(jié)論：特比萘芬治療甲真菌病成本效果比優(yōu)于伊曲康唑。關(guān)鍵詞 特比萘芬；伊曲康唑；甲真菌??；藥物經(jīng)濟(jì)學(xué)；成本-

2、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(guó)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(xué)的方法對(duì)特比萘芬和伊曲康唑治療甲真菌病的療效進(jìn)行meta分析，并進(jìn)一步作兩種藥物的經(jīng)濟(jì)學(xué)評(píng)價(jià)。1 材料1.1費(fèi)用計(jì)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(shè)所有患者所進(jìn)行的檢驗(yàn)費(fèi)用相同，為了能較好的反應(yīng)藥物與療效的關(guān)系，只計(jì)算藥品直接成本。藥品價(jià)格為“2002年濟(jì)南市衛(wèi)生局藥品集中招標(biāo)采購”中標(biāo)零售價(jià)。特比萘芬（

3、進(jìn)口：蘭美抒，北京諾華制藥有限公司，規(guī)格：0.25g7片，單價(jià)：￥118.40/盒；國(guó)產(chǎn)：丁克，齊魯制藥廠，規(guī)格：0.125g6片，單價(jià)：￥48.00/盒）；伊曲康唑（進(jìn)口：斯皮仁諾，西安楊森制藥有限公司，規(guī)格：0.1g14片，單價(jià)：￥144.30/盒；國(guó)產(chǎn)：伊曲康唑膠囊，成都倍特藥業(yè)有限公司，規(guī)格：0.1g14片，單價(jià)：￥115.00/盒）。1.2臨床材料 利用Internet 網(wǎng)絡(luò)資源：MEDLINE網(wǎng)站連接（ PubMed）、檢索關(guān)鍵詞：(terbinafine OR itraconazole ) AND onychomycosis。納入標(biāo)準(zhǔn)：隨機(jī)對(duì)照試驗(yàn)，無論是否采取盲法；試驗(yàn)至少納入

4、一平行的對(duì)照組接受安慰劑對(duì)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(píng)價(jià)應(yīng)包括臨床治愈和微生物學(xué)檢查治愈。按循證醫(yī)學(xué)方法篩選臨床證據(jù)可靠性符合級(jí)別和級(jí)別文獻(xiàn)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（P0.05），明顯優(yōu)于伊曲康唑沖擊療法（P0.01）。2 成本-效果分析 目前應(yīng)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(fèi)用和效果，在其間找到一個(gè)最佳點(diǎn)。特比萘芬每獲得一

5、個(gè)治療單位需￥19.45，與伊曲康唑沖擊療法（￥18.05）相當(dāng)，遠(yuǎn)小于伊曲康唑（￥25.89）連續(xù)用藥。特比萘芬比伊曲康唑沖擊療法每多獲得一個(gè)治療單位需￥22.12，小于伊曲康唑連續(xù)用藥（￥45.74），見表4。3 敏感度分析 國(guó)產(chǎn)特比萘芬與進(jìn)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(jì)學(xué)上均無顯著性差異34，35，國(guó)產(chǎn)伊曲康唑膠囊劑相對(duì)進(jìn)口斯皮仁諾膠囊的生物利用度為102.27%。該制劑與同類進(jìn)口產(chǎn)品為等效制劑36。國(guó)產(chǎn)兩種藥物臨床療效和安全性與進(jìn)口藥相當(dāng)，但價(jià)格有一定程度下降，所以，按國(guó)產(chǎn)特比萘芬片劑、伊曲康唑膠囊劑價(jià)格進(jìn)行敏感度分析。計(jì)算得表5?？梢妵?guó)產(chǎn)進(jìn)口特比萘芬價(jià)格相差

6、無幾，每日劑量/費(fèi)用：特比萘芬進(jìn)口0.25g /￥16.91、國(guó)產(chǎn)0.25g /￥16.00，差價(jià)￥0.91，降幅5.38%；伊曲康唑相差較大，連續(xù)用藥進(jìn)口0.2 g /￥20.61、國(guó)產(chǎn)0.2 g /￥16.43，差價(jià)￥4.18，沖擊療法進(jìn)口0.4 g /￥41.22、國(guó)產(chǎn)0.4g /￥32.86，差價(jià)￥8.36，降幅20.28%。兩種藥物雖有不同程度的下降，但對(duì)分析結(jié)果沒有發(fā)生質(zhì)的影響。4 討論 特比萘芬結(jié)構(gòu)中有烯丙胺結(jié)構(gòu)，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(xì)胞中蓄積，破壞了真菌的膜結(jié)構(gòu)，使其中主要成分如磷脂及蛋白質(zhì)的合成與轉(zhuǎn)換功能明顯減退，膜功能的降低導(dǎo)致

7、真菌死亡。人體細(xì)胞對(duì)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(duì)皮膚真菌有殺菌作用，對(duì)白色念珠菌則起抑菌作用。特比萘芬通過甲床和甲母質(zhì)兩條途徑向甲中進(jìn)行擴(kuò)散，進(jìn)入指甲的藥物能以較高的濃度存在較長(zhǎng)的時(shí)間，停藥后8周12周甲中藥物濃度明顯高于特比萘芬對(duì)皮膚癬菌的MIC37。伊曲康唑是一合成廣譜抗真菌藥，為三氯唑衍生物。對(duì)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(guān)，它是通過抑制真菌細(xì)胞膜的必需成分麥角固醇的合成而抑制真菌生長(zhǎng)的。伊曲康唑在皮膚內(nèi)的藥代動(dòng)力學(xué)比較獨(dú)特，其主要通過皮脂輸送，導(dǎo)致其皮膚內(nèi)濃度高于血漿內(nèi)倍，因此適于對(duì)皮膚真菌感染的治療，尤其是指（趾）甲的感

8、染。治療開始不久就可在甲片和甲床遠(yuǎn)端檢測(cè)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(zhǎng)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(yīng)用方便。特比萘芬（治愈率：73.0516.73）臨床療效優(yōu)于伊曲康唑（治愈率：連續(xù)用藥66.8915.82，沖擊療法47.9625.56），治療成本低于伊曲康唑連續(xù)用藥，因此可以認(rèn)為特比萘芬治療甲真菌病較伊曲康唑更經(jīng)濟(jì)實(shí)惠。由于特比萘芬國(guó)產(chǎn)化比較早，幾乎與進(jìn)口藥同時(shí)上市，價(jià)格較低、差價(jià)較小，每日劑量費(fèi)用國(guó)產(chǎn)進(jìn)口僅相差0.91元，降幅5.38%；伊曲康唑一直僅有進(jìn)

9、口商品占領(lǐng)市場(chǎng)，國(guó)產(chǎn)藥品2002年剛剛上市，價(jià)格較高、差價(jià)較大，每日劑量費(fèi)用差價(jià)連續(xù)用藥4.18元，沖擊療法8.36元，降幅20.28%，。特比萘芬每獲得一個(gè)治療單位需￥19.45，與伊曲康唑沖擊療法（￥18.05）相當(dāng)，遠(yuǎn)小于伊曲康唑（￥25.89）連續(xù)用藥。特比萘芬比伊曲康唑沖擊療法每多獲得一個(gè)治療單位需￥22.12，小于伊曲康唑連續(xù)用藥（￥45.74）。當(dāng)應(yīng)用國(guó)產(chǎn)兩種藥物治療時(shí)，費(fèi)用相當(dāng)，特比萘芬每獲得一個(gè)治療單位需￥18.40，伊曲康唑連續(xù)用藥（￥20.63）沖擊療法（￥14.39）。敏感度分析結(jié)果顯示兩種藥物降價(jià)后，對(duì)分析結(jié)果沒有發(fā)生質(zhì)的影響。分析結(jié)果顯示：特比萘芬治療甲真菌病成本效

10、果比優(yōu)于伊曲康唑。同時(shí)還可看到市場(chǎng)競(jìng)爭(zhēng)的作用以及壯大國(guó)有企業(yè)的重要性。參考文獻(xiàn)1 Arca E, Tastan HB, Akar A, et al. An open, randomized, comparative study of oral fluconazole, itraconazole and terbinafine therapy in onychomycosis.J Dermatolog Treat, 2002, 13(1):3-92Salo H, Pekurinen M. Cost effectiveness of oral terbinafine (Lamisil) compa

11、red with oral fluconazole (Diflucan) in the treatment of patients with toenail onychomycosis. Pharmacoeconomics, 2002, 20(5):319-3243 Sigurgeirsson B, Olafsson JH, Steinsson JB, et al. Long-term effectiveness of treatment with terbinafine vs itraconazole in onychomycosis: a 5-year blinded prospectiv

12、e follow-up study. Arch Dermatol, 2002, 138(3):353-3574 Gupta AK, Gregurek-Novak T. Efficacy of itraconazole, terbinafine, fluconazole, griseofulvin and ketoconazole in the treatment of Scopulariopsis brevicaulis causing onychomycosis of the toes. Dermatology, 2001, 202(3):235-2385 Gupta AK, Lynde C

13、W, Konnikov N. Single-blind, randomized, prospective study of sequential itraconazole and terbinafine pulse compared with terbinafine pulse for the treatment of toenail onychomycosis.J Am Acad Dermatol, 2001, 44(3):485-4916 Gupta AK, Konnikov N, Lynde CW. Single-blind, randomized, prospective study

14、on terbinafine and itraconazole for treatment of dermatophyte toenail onychomycosis in the elderly.J Am Acad Dermatol, 2001, 44(3):479-4847 Sigurgeirsson B, Billstein S, Rantanen T, et al. L.I.ON. Study: efficacy and tolerability of continuous terbinafine (Lamisil)compared to intermittent itraconazo

15、le in the treatment of toenail onychomycosis. Lamisil vs. Itraconazole in Onychomycosis. Br J Dermatol, 1999, 141(Suppl 56):5-148 Havu V, Heikkila H, Kuokkanen K, et al. A double-blind, randomized study to compare the efficacy and safety of terbinafine (Lamisil) with fluconazole (Diflucan) in the tr

16、eatment of onychomycosis. Br J Dermatol, 2000, 142(1):97-1029 Kejda J. Itraconazole pulse therapy vs continuous terbinafine dosing for toenail onychomycosis.Postgrad Med, 1999, Spec No:12-1510 Degreef H, del Palacio A, Mygind S, et al. Randomized double-blind comparison of short-term itraconazole an

17、d terbinafine therapy for toenail onychomycosis. Acta Derm Venereol, 1999, 79(3):221-22311Evans EG, Sigurgeirsson B. Double blind, randomised study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis. BMJ, 1999, 318(7190):1031-103512Drake LA, Shear

18、 NH, Arlette JP,et al. Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial. J Am Acad Dermatol, 1997, 37(5 Pt 1):740-74513Tausch I, Brautigam M, Weidinger G, et al. Evaluation of 6 weeks treatment of terbinafine in tinea unguium in a double-blind trial compar

19、ing 6 and 12 weeks therapy. Br J Dermatol, 1997, 136(5):737-74214Ellis DH, Watson AB, Marley JE, et al. Non-dermatophytes in onychomycosis of the toenails. Br J Dermatol, 1997, 136(4):490-3.15Alpsoy E, Yilmaz E, Basaran E. Intermittent therapy with terbinafine for dermatophyte toe-onychomycosis: a n

20、ew approach. J Dermatol. 1996 ,23(4):259-62.16Tosti A, Piraccini BM, Stinchi C, et al. Treatment of dermatophyte nail infections: an open randomized study comparing intermittent terbinafine therapy with continuous terbinafine treatment and intermittent itraconazole therapy. J Am Acad Dermatol, 1996,

21、 34(4):595-60017De Backer M, De Keyser P, De Vroey C, et al. A 12-week treatment for dermatophyte toe onychomycosis: terbinafine 250 mg/day vs. itraconazole 200 mg/day-a double-blind comparative trial. Br J Dermatol, 1996, 134 (Suppl 46):16-7: discussion 3818Watson A, Marley J, Ellis D, et al. Terbi

22、nafine in onychomycosis of the toenail: a novel treatment protocol. J Am Acad Dermatol, 1995, 33(5 Pt 1):775-77919Brautigam M, Nolting S, Schopf RE, et al. Randomised double blind comparison of terbinafine and itraconazole for treatment of toenail tinea infection. Seventh Lamisil German Onychomycosi

23、s Study Group. BMJ, 1995, 311(7010):919-92220Faergemann J, Anderson C, Hersle K, et al. Double-blind, parallel-group comparison of terbinafine and griseofulvin in the treatment of toenail onychomycosis. J Am Acad Dermatol, 1995, 32(5 Pt 1):750-75321Arenas R, Dominguez-Cherit J, Fernandez LM. Open ra

24、ndomized comparison of itraconazole versus terbinafine in onychomycosis. Int J Dermatol, 1995, 34(2):138-14322Goodfield MJ, Andrew L, Evans EG. Short term treatment of dermatophyte onychomycosis with terbinafine. BMJ,1992, 304(6835):1151-115423van der Schroeff JG, Cirkel PK, Crijns MB, et al. A rand

25、omized treatment duration-finding study of terbinafine in onychomycosis. Br J Dermatol, 1992, 126 (Suppl 39):36-3924Savin RC. Oral terbinafine versus griseofulvin in the treatment of moccasin-type tinea pedis. J Am Acad Dermatol, 1990, 23(4 Pt 2):807-80925Lecha M. Amorolfine and itraconazole combina

26、tion for severe toenail onychomycosis; results of an open randomized trial in Spain. Br J Dermatol, 2001, 145(Suppl 60):21-2626Elewski BE, Scher RK, Aly R, et al. Double-blind, randomized comparison of itraconazole capsules vs. placebo in the treatment of toenail onychomycosis. Cutis, 1997, 59(4):21

27、7-22027Haneke E, Delescluse J, Plinck E, et al. The use of itraconazole in onychomycosis. Eur J Dermatol, 1996,6:7-1028Haneke E, Tajerbashi M, De doncker P, et al. Itraconazole in the treatment of onychomycosis: a double-blind comparison with miconazole. Dermatology,1998,196:323-32929Havu V, Brandt

28、H, Heikkila H, et al. A double-blind, randomized study comparing itraconazole pulse therapy with continuous dosing for the treatment of toe-nail onychomycosis. Br J Dermatol, 1997, 136(2):230-23430Honeyman JF, Talarico FS, Arruda LHF, et al. Itraconazole versus terbinafine(Lamisil):which is better f

29、or the treatment of onychomycosis?J Eur Acad Dermatol, 1997, 9:215-22131Jones HE, Zaias N. Double-blind, randomized comparison of itraconazole capsules and placebo in the treatment of onychomycosis of the toenail. Int J Dermatol, 1996, 35:589-59032Odom R, Daniel CR, Aly R. A double-blind, randomized

30、 comparison of itraconazole capsules and placebo in the treatment of onychomycosis of the toenail. J Am Acad Dermatol, 1996, 35(1):110-11133Itraconazole product monopraph. Titusville(NJ):Janssen Pharmaceutica Inc.,199634王愛平，李若瑜，王瑞禮，等特比萘芬片劑治療淺部真菌病隨機(jī)雙盲對(duì)照多中心臨床試驗(yàn)中國(guó)臨床藥理學(xué)雜志，1997，13（2）：71-7735顧菊琳，廖萬清，秦萬章，等

31、特比萘芬軟膏與療霉舒軟膏隨機(jī)對(duì)照治療淺部真菌病多中心臨床研究中國(guó)皮膚性病雜志，1999，13（5）：274-27636傅強(qiáng)，朱珠，劉海凈，等國(guó)產(chǎn)伊曲康唑膠囊劑的生物等效性研究中國(guó)藥學(xué)雜志，2001，36（5）：323-32537 劉偉，李若瑜，陳瓊，等高效液相色譜法測(cè)定指甲真菌病患者甲中特比萘芬水平的研究中國(guó)臨床藥理學(xué)雜志，1999，15（6）：435-439Table 1 Studies used in the mata-analysis to calculate cure rate when terbinafine is used to treat onychomycosisAutherT

32、ype of StudyDosage(mg/d)ncCure rate(%)Arca E1Open ,randomized,comparative250161062.50Salo H2Double-blind,randomized,comparative250483266.67Sigurgeirsson B3Double-blind,randomized,comparative250743445.95Gupta AK4Single-blind,randomized,comparative250121191.67Gupta AK5Single-blind,randomized,comparati

33、ve250902932.22Gupta AK6Single-blind,randomized,comparative250503162.00Sigurgeirsson B7Double-blind,randomized,comparative2501078175.70Havu V8Double-blind,randomized,placebo-controlled250464189.13Kejda J9Open ,randomized,comparative25016212375.93Degreef H10Double-blind,randomized,comparative250146986

34、7.12Evans EG11Double-blind,randomized,comparative2501078175.70Drake LA12Double-blind,randomized,placebo-controlled25035826574.02Tausch I13Double-blind,randomized,comparative250765572.37Ellis DH14Double-blind,randomized,placebo-controlled2501184235.59Alpsoy E15Open ,randomized,comparative250241979.17

35、Tosti A16Open ,randomized,comparative250171694.12De Backer M17Double-blind,randomized,comparative25016311973.01Watson A18Double-blind,randomized,comparative250564987.50Brautigam M19Double-blind,randomized,comparative250867081.40Faergemann J20Double-blind,randomized,comparative250433683.72Arenas R21O

36、pen ,randomized,comparative2501717100.00Goodfield MJ22Double-blind,randomized,comparative250453782.22van der Schroeff JG23Double-blind,randomized,comparative250342470.59Savin RC24Double-blind,randomized,comparative250161275.00Table 2 Studies used in the mata-analysis to calculate cure rate when itra

37、conazole is used to treat onychomycosisAutherType of StudyDosage(mg/d)ncCure rate(%)Arca E1Open ,randomized,comparative200181161.11Gupta AK4Single-blind,randomized,comparative2001212100.00Gupta AK5Single-blind,randomized,comparative200753952.00Gupta AK6Single-blind,randomized,comparative200513160.78

38、Degreef H10Double-blind,randomized,comparative2001468960.96Watson A18Double-blind,randomized,comparative2007718641.40Brautigam M19Double-blind,randomized,comparative200845363.10Arenas R21Open ,randomized,comparative200232295.65Lecha M25Open ,randomized,comparative200322268.75Elewski BE26Double-blind

39、,randomized,comparative2001095954.13Haneke E27randomized,comparative20018814778.19Haneke E28Double-blind,randomized,comparative20054040074.07Havu V29Double-blind,randomized,comparative200624166.13Honeyman JF30Double-blind,randomized,comparative200837185.54Jones HE31Double-blind,randomized,placebo-co

40、ntrolled200352468.57Odom R32Double-blind,randomized,placebo-controlled200381847.37US product monopraph33Double-blind,randomized,placebo-controlled2001105953.64Sigurgeirsson B3Double-blind,randomized,comparative400771012.99Sigurgeirsson B7Double-blind,randomized,comparative4001074138.32Kejda J9Open ,

41、randomized,comparative40015311575.16Evans EG11Double-blind,randomized,comparative4001074138.32Tosti A16Open ,randomized,comparative400201575.00Havu V28Double-blind,randomized,comparative400594169.49Tab 3 Rank sum test of itraconazole and terbinafine in onychomycosisGroup Rank sum of difference SRARB

42、 q P1 and 3 989.5 3 96.22 10.28 0.011 and 2 4 2 64.37 0.67 0.052 and 3 985.5 2 41.06 24.00 0.01Drug Regimen Cost（C） Cure rate（E，%） 95% confidence interval C/E C/Eterbinafine 250mg/d12weeks 1420.80 73.0516.73 72.3073.80 19.45 22.12itraconazole 200mg/d12weeks 1731.60 66.8915.82 66.1167.69 25.89 45.74

43、200mg b.i.d,1 week3pulses 865.80 47.9625.56 45.9749.95 18.05 Tab 4 Cost-effectiveness analysis(￥) Tab 5 Analysis of semsitivities(￥) Drug Regimen Cost（C） Cure rate（E，%） C/E C/Eterbinafine 250mg/d12weeks 1344.00 73.0516.73 18.4026.07itraconazole 200mg/d12weeks 1380.00 66.8915.82 20.63 36.45 200mg b.i.d,1 week3pulses 690.00 47.9625.56 14.39 Cost-effectiveness analysis s of terbinafine and itraconazole in onychomycosisYAN Jun (Jinan city hospital for s