特比萘芬和伊曲康唑治疗甲真菌病的成本—效果分析摘要目的：评价应用特比萘芬与伊曲康唑治疗甲真菌病的经济效果。
方法：采用循证医学的方法自MEDLINE收集临床资料，应用药物经济学的成本-效果分析法对特比萘芬与伊曲康唑治疗甲真菌病进行评价。
结果：两种药物甲真菌病治愈率meta-分析显示：特比萘芬（73.05±16.73）和伊曲康唑连续用药（66.89±15.82）、冲击疗法（47.96±25.56），治疗费用特比萘芬（￥1420.80）和伊曲康唑连续用药（￥1731.6）、冲击疗法（￥865.80）。
结论：特比萘芬治疗甲真菌病成本效果比优于伊曲康唑。
关键词特比萘芬；伊曲康唑；甲真菌病；药物经济学；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组织所引起的病变。
常见致病菌：皮肤癣菌、酵母菌、白色念珠菌等，通常由皮肤癣菌引起的病变称甲癣。
本文我国患病率约4%~7%，以红色毛癣菌、石膏样毛癣菌多见。
本文借助循证医学的方法对特比萘芬和伊曲康唑治疗甲真菌病的疗效进行meta—分析，并进一步作两种药物的经济学评价。
1 材料1.1费用计算甲真菌病为局部感染性炎症，一般无全身症状，无须住院治疗，特比萘芬和伊曲康唑口服吸收良好，无须特殊给药方法，假设所有患者所进行的检验费用相同，为了能较好的反应药物与疗效的关系，只计算药品直接成本。
药品价格为“2002年济南市卫生局药品集中招标采购”中标零售价。
特比萘芬（进口：兰美抒，北京诺华制药有限公司，规格：0.25g×7片，单价：￥118.40/盒；国产：丁克，齐鲁制药厂，规格：0.125g×6片，单价：￥48.00/盒）；伊曲康唑（进口：斯皮仁诺，西安杨森制药有限公司，规格：0.1g×14片，单价：￥144.30/盒；国产：伊曲康唑胶囊，成都倍特药业有限公司，规格：0.1g×14片，单价：￥115.00/盒）。
1.2临床材料利用Internet 网络资源：MEDLINE网站连接（/ PubMed）、检索关键词：(terbinafine OR itraconazole ) AND onychomycosis。
纳入标准：随机对照试验，无论是否采取盲法；试验至少纳入一平行的对照组接受安慰剂对照或药物（特比萘芬、伊曲康唑、氟康唑、灰黄霉素）治疗；使用单一特比萘芬或伊曲康唑治疗无合并用药（包括外用药物）；治疗评价应包括临床治愈和微生物学检查治愈。
按循证医学方法筛选临床证据可靠性符合级别Ⅰ和级别Ⅱ文献33篇。
见表1，表2，表3。
特比萘芬临床疗效优于伊曲康唑连续用药疗法（P＞0.05），明显优于伊曲康唑冲击疗法（P＜0.01）。
2 成本-效果分析目前应用较普遍的治疗甲真菌病口服药物有特比萘芬、伊曲康唑、氟康唑、灰黄霉素等4种，以特比萘芬和伊曲康唑治疗效果及安全性较佳[1，2，4，8，23]。
成本-效果分析的目的在于平衡治疗费用和效果，在其间找到一个最佳点。
特比萘芬每获得一个治疗单位需￥19.45，与伊曲康唑冲击疗法（￥18.05）相当，远小于伊曲康唑（￥25.89）连续用药。
特比萘芬比伊曲康唑冲击疗法每多获得一个治疗单位需￥22.12，小于伊曲康唑连续用药（￥45.74），见表4。
3 敏感度分析国产特比萘芬与进口特比萘芬无论口服制剂还是外用制剂临床疗效和安全性在统计学上均无显著性差异[34，35]，国产伊曲康唑胶囊剂相对进口斯皮仁诺胶囊的生物利用度为102.27%。
该制剂与同类进口产品为等效制剂[36]。
国产两种药物临床疗效和安全性与进口药相当，但价格有一定程度下降，所以，按国产特比萘芬片剂、伊曲康唑胶囊剂价格进行敏感度分析。
计算得表5。
可见国产进口特比萘芬价格相差无几，每日剂量/费用：特比萘芬进口0.25g /￥16.91、国产0.25g /￥16.00，差价￥0.91，降幅5.38%；伊曲康唑相差较大，连续用药进口0.2 g /￥20.61、国产0.2 g /￥16.43，差价￥4.18，冲击疗法进口0.4 g /￥41.22、国产0.4g /￥32.86，差价￥8.36，降幅20.28%。
两种药物虽有不同程度的下降，但对分析结果没有发生质的影响。
4 讨论特比萘芬结构中有烯丙胺结构，能抑制真菌麦角甾醇合成过程中角鲨烯环氧化酶的作用。
致使角鲨烯在真菌细胞中蓄积，破坏了真菌的膜结构，使其中主要成分如磷脂及蛋白质的合成与转换功能明显减退，膜功能的降低导致真菌死亡。
人体细胞对本品的敏感性为真菌的万分之一。
本品有广谱抗真菌作用，对皮肤真菌有杀菌作用，对白色念珠菌则起抑菌作用。
特比萘芬通过甲床和甲母质两条途径向甲中进行扩散，进入指甲的药物能以较高的浓度存在较长的时间，停药后8周~12周甲中药物浓度明显高于特比萘芬对皮肤癣菌的MIC[37]。
伊曲康唑是一合成广谱抗真菌药，为三氯唑衍生物。
对皮肤癣菌、酵母菌、曲霉菌等真菌感染有效。
其广谱抗菌活性与给药方式无关，它是通过抑制真菌细胞膜的必需成分—麦角固醇的合成而抑制真菌生长的。
伊曲康唑在皮肤内的药代动力学比较独特，其主要通过皮脂输送，导致其皮肤内浓度高于血浆内５~１０倍，因此适于对皮肤真菌感染的治疗，尤其是指（趾）甲的感染。
治疗开始不久就可在甲片和甲床远端检测到伊曲康唑，并且其保留在甲中不循环回血，直至因指甲自然生长而使其浓度降低，故无须持续给药。
特比萘芬和伊曲康唑无论治疗效果还是安全性均优于目前治疗甲真菌病的其他药物[1，2，4，8，23]，并且携带、应用方便。
特比萘芬（治愈率：73.05±16.73）临床疗效优于伊曲康唑（治愈率：连续用药66.89±15.82，冲击疗法47.96±25.56），治疗成本低于伊曲康唑连续用药，因此可以认为特比萘芬治疗甲真菌病较伊曲康唑更经济实惠。
由于特比萘芬国产化比较早，几乎与进口药同时上市，价格较低、差价较小，每日剂量费用国产进口仅相差0.91元，降幅5.38%；伊曲康唑一直仅有进口商品占领市场，国产药品2002年刚刚上市，价格较高、差价较大，每日剂量费用差价连续用药4.18元，冲击疗法8.36元，降幅20.28%，。
特比萘芬每获得一个治疗单位需￥19.45，与伊曲康唑冲击疗法（￥18.05）相当，远小于伊曲康唑（￥25.89）连续用药。
用国产两种药物治疗时，费用相当，特比萘芬每获得一个治疗单位需￥18.40，伊曲康唑连续用药（￥20.63）冲击疗法（￥14.39）。
敏感度分析结果显示两种药物降价后，对分析结果没有发生质的影响。
分析结果显示：特比萘芬治疗甲真菌病成本效果比优于伊曲康唑。
同时还可看到市场竞争的作用以及壮大国有企业的重要性。
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Titusville(NJ):Janssen Pharmaceutica Inc.,1996[34]王爱平，李若瑜，王瑞礼，等．特比萘芬片剂治疗浅部真菌病随机双盲对照多中心临床试验．中国临床药理学杂志，1997，13（2）：71-77[35]顾菊琳，廖万清，秦万章，等．特比萘芬软膏与疗霉舒软膏随机对照治疗浅部真菌病多中心临床研究．中国皮肤性病杂志，1999，13（5）：274-276[36]傅强，朱珠，刘海净，等．国产伊曲康唑胶囊剂的生物等效性研究．中国药学杂志，2001，36（5）：323-325[37] 刘伟，李若瑜，陈琼，等．高效液相色谱法测定指甲真菌病患者甲中特比萘芬水平的研究．中国临床药理学杂志，1999，15（6）：435-439Table 1 Studies used in the mata-analysis to calculate cure rate when terbinafine is used to treat onychomycosis Auther Type of Study Dosage(mg/d) n c Cure rate(%) Arca E[1]Open ,randomized,comparative 250 161062.50 Salo H[2]Double-blind,randomized,comparative 250 48 32 66.67 Sigurgeirsson B[3]Double-blind,randomized,comparative 250 743445.95 Gupta AK[4]Single-blind,randomized,comparative 250 121191.67 Gupta AK[5]Single-blind,randomized,comparative 250 902932.22 Gupta AK[6]S ingle-blind,randomized,comparative 250 503162.00 Sigurgeirsson B[7]Double-blind,randomized,comparative 250 1078175.70 Havu V[8]Double-blind,randomized,placebo-controlled 250 464189.13 Kejda J[9]Open ,randomized,comparative 250 16212375.93 Degreef H[10]Double-blind,randomized,comparative 250 1469867.12 Evans EG[11]Double-blind,randomized,comparative 250 1078175.70 Drake LA[12]Double-blind,randomized,placebo-controlled 250 35826574.02 Tausch I[13]Double-blind,randomized,comparative 250 765572.37 Ellis DH[14]Double-blind,randomized,placebo-controlled 250 1184235.59 Alpsoy E[15]Open ,randomized,comparative 250 241979.17 Tosti A[16]Open ,randomized,comparative 250 171694.12De Backer M[17]Double-blind,randomized,comparative 250 16311973.01 Watson A[18]Double-blind,randomized,comparative 250 564987.50 Brautigam M[19]Double-blind,randomized,comparative 250 867081.40 Faergemann J[20]Double-blind,randomized,comparative 250 433683.72 Arenas R[21]Open ,randomized,comparative 250 1717100.00 Goodfield MJ[22]Double-blind,randomized,comparative 250 453782.22 van der Schroeff JG[23]Double-blind,randomized,comparative 250 342470.59 Savin RC[24]Double-blind,randomized,comparative 250 161275.00Table 2 Studies used in the mata-analysis to calculate cure rate when itraconazole is used to treat onychomycosis Auther Type of Study Dosage(mg/d) n c Cure rate(%) Arca E[1]Open ,randomized,comparative 200 181161.11 Gupta AK[4]Single-blind,randomized,comparative 200 1212100.00 Gupta AK[5]Single-blind,randomized,comparative 200 753952.00 Gupta AK[6]Single-blind,randomized,comparative 200 513160.78 Degreef H[10]Double-blind,randomized,comparative 200 1468960.96 Watson A[18]Double-blind,randomized,comparative 200 7718641.40 Brautigam M[19]Double-blind,randomized,comparative 200 845363.10 Arenas R[21]Open ,randomized,comparative 200 232295.65 Lecha M[25]Open ,randomized,comparative 200 322268.75 Elewski BE[26]Double-blind,randomized,comparative 200 1095954.13 Haneke E[27]randomized,comparative 200 18814778.19 Haneke E[28]Double-blind,randomized,comparative 200 54040074.07 Havu V[29]Double-blind,randomized,comparative 200 624166.13 Honeyman JF[30]Double-blind,randomized,comparative 200 837185.54 Jones HE[31]Double-blind,randomized,placebo-controlled 200 352468.57 Odom R[32]Double-blind,randomized,placebo-controlled 200 381847.37 US product monopraph[33]Double-blind,randomized,placebo-controlled 200 1105953.64 Sigurgeirsson B[3]Double-blind,randomized,comparative 400 771012.99 Sigurgeirsson B[7]Double-blind,randomized,comparative 400 1074138.32 Kejda J[9]Open ,randomized,comparative 400 15311575.16 Evans EG[11]Double-blind,randomized,comparative 400 1074138.32 Tosti A[16]Open ,randomized,comparative 400 201575.00 Havu V[28]Double-blind,randomized,comparative 400 594169.49Tab 3Rank sum test of itraconazole and terbinafine in onychomycosisGroup Rank sum of difference αS R A－R B q P1 and 3 989.5 3 96.22 10.28 ＜0.011 and2 4 2 64.37 0.67 ＞0.052 and3 985.5 2 41.06 24.00 ＜0.01Tab 4 Cost-effectiveness analysis(￥)Drug Regimen Cost（C）Cure rate（E，%）95% confidence interval C/E ΔC/ΔE terbinafine 250mg/d×12weeks 1420.80 73.05±16.73 72.30~73.80 19.45 22.12 itraconazole 200mg/d×12weeks 1731.60 66.89±15.82 66.11~67.69 25.89 45.74 200mg b.i.d,1 week×3pulses 865.80 47.96±25.56 45.97~49.95 18.05 —Tab 5 Analysis of semsitivities(￥)Drug Regimen Cost（C）Cure rate（E，%）C/E ΔC/ΔE terbinafine 250mg/d×12weeks 1344.00 73.05±16.73 18.40 26.07 itraconazole 200mg/d×12weeks 1380.00 66.89±15.82 20.63 36.45 200mg b.i.d,1 week×3pulses 690.00 47.96±25.56 14.39 —Cost-effectiveness analysis s of terbinafine and itraconazole in onychomycosisYAN Jun (Jinan city hospital for skin diseases prevention and treatment, Jinan 250001)ABSTRACT OBJECTIVE: To determine the pharmacoeconomic of terbinafine tablets compared with itraconazole capsules in the treatment of patients with onychomycosis. METHODS: The clinical data of terbinafine and itraconazole in onychomycosis were collected with evidence based medicine from MEDLINE.Terbinafine 250 mg/d for 12 weeks (n = 1911) was compared with itraconazole 200mg/d for 12 weeks(n = 1683) or 200mg, b.i.d for 1 week×3 pulses (n = 523) in patients with culture-confirmed onychomycosiscaused by dermatophyte infection. We subsequently used these data to calculate the cost effectiveness of the three treatment regimens. RESULTS: For each comparator the meta-analytic average cure rate were: terbinafine (73.05±16.73), itraconazole (continuous) (66.89±15.82), and itraconazole (pulse) (47.96±25.56). The cost of regimen for the drug comparators was: terbinafine ￥1420.80, itraconazole (continuous) ￥1731.60, and itraconazole (pulse) ￥865.80. CONCLUSIONS: The clinical study showed that terbinafine was more effective than itraconazole in the treatment of onychomycosis, achieving higher rates cure. Based on the patient-level analysis, we concluded that terbinafine is the most cost-effective therapy in the treatment of onychomycosis.KEY WORDS terbinafine; itraconazole; onychomycosis; pharmacoeconomic ; cost-effectiveness analysis。