10注射用阿尼芬净.docx

1、10注射用阿尼芬净阿尼芬净注射液（Anidulafungin/Eraxis）FDA批准阿尼芬净治疗念珠菌感染关键字：阿尼芬净注射液（Anidulafungin/Eraxis）FDA批准了Eraxis(通用名：阿尼芬净anidulafungin)用于治疗假丝酵母（Candida）引起的某些感染。Candida是一种能在就医病人或免疫系统受损的病人中引起严重感染的类似酵母的真菌。“该产品为与假丝酵母相关的几种感染提供了一种新的可选疗法”，FDA的药品评价与研究中心主任Steven Galson博士称。“它是现有用于治疗这些潜在的严重真菌病症的抗菌药物的有益补充。”一种从未在美国上市的新分子实体Er

2、axis，是一种静脉注射的抗真菌药物，并被用于治疗食道（念珠菌病）、血液（念珠菌血症）中的假丝酵母感染以及其他类型的假丝酵母感染，包括腹部脓肿和腹膜炎（腹腔内壁发炎）。临床研究评价了Eraxis的安全性和有效性，并且显示Eraxis在食道念珠菌病、念珠菌血症（candidemia）以及其他包括腹部脓肿和腹膜炎在内的假丝酵母感染的治疗中是安全且有效的。Eraxis在临床研究中普遍很耐受。最常见报告的不良事件是：轻度腹泻，肝酶的实验室测试水平轻微上升，以及头痛。一些病人经历了与输液相关的反应，其中多数为轻度。在具有重大的潜在医学状况的且正伴服多重药物的少数病人中，有严重肝异常的报道。Eraxis由

3、纽约州的Pfizer公司生产。ERAXIS - anidulafungininjection, powder, lyophilized, for solutionRoerigERAXIS (anidulafungin) FOR INJECTIONINTRAVENOUS INFUSION, DILUTED WITH STERILE WATER FOR INJECTION (not for IV Bolus Injection)DESCRIPTIONERAXIS for Injection is a sterile, lyophilized product for intravenous (IV)

4、 infusion that contains anidulafungin. ERAXIS (anidulafungin) is a semi-synthetic lipopeptide synthesized from a fermentation product ofAspergillusnidulans. Anidulafungin is an echinocandin, a class of antifungal drugs that inhibits the synthesis of 1,3-D-glucan, an essential component of fungal cel

5、l walls.ERAXIS (anidulafungin) is 1-(4R,5R)-4,5-dihydroxy-N2-4-(pentyloxy)1,1:4,1-terphenyl-4-ylcarbonyl-L-ornithineechinocandin B.Anidulafungin is a white to off-white powder that is practically insoluble in water and slightly soluble in ethanol. In addition to the active ingredient, anidulafungin,

6、 ERAXIS for Injection contains the following inactive ingredients:50 mg/vial- fructose (50 mg), mannitol (250 mg), polysorbate 80 (125 mg), tartaric acid (5.6 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.100 mg/vial- fructose (100 mg), mannitol (500 mg), polysorbate 80 (250 m

7、g), tartaric acid (11.2 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.The empirical formula of anidulafungin is C58H73N7O17and the formula weight is 1140.3.The structural formula is:Prior to administration, ERAXIS for Injection requires reconstitution with sterile Water for In

8、jection and subsequent dilution with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline).DO NOT dilute with other solutions or co-infuse with other medications or electrolytes (seeDOSAGE AND ADMINISTRATION).CLINICAL PHARMACOLOGYPharmacokineticsThe pharmacokinetic

9、s of anidulafungin following IV administration have been characterized in healthy subjects, special populations and patients. Systemic exposures of anidulafungin are dose-proportional and have low intersubject variability (coefficient of variation 99%) to human plasma proteins.MetabolismHepatic meta

10、bolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 (CYP450) isoenzymes. It is unlikely that anidulafungin will have clinically relevant effects on the metabolism of drugs metabolized by CYP450 isoenzymes.Anidu

11、lafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-opened peptide that lacks antifungal activity. Thein vitrodegradation half-life of anidulafungin under physiologic conditions is about 24 hours.In vivo, the ring-opened product is subsequently converted to pepti

12、dicdegradants and eliminated.ExcretionIn a single-dose clinical study, radiolabeled (14C) anidulafungin was administered to healthy subjects. Approximately 30% of the administered radioactive dose was eliminated in the feces over 9 days, of which less than 10% was intact drug. Less than 1% of the ad

13、ministered radioactive dose was excreted in the urine. Anidulafungin concentrations fell below the lower limits of quantitation 6 days post-dose. Negligible amounts of drug-derived radioactivity were recovered in blood, urine, and feces 8 weeks post-dose.Special PopulationsPatients with fungal infec

14、tionsPopulation pharmacokinetic analyses from four Phase 2/3 clinical studies including 107 male and 118 female patients with fungal infections showed that the pharmacokinetic parameters of anidulafungin are not affected by age, race, or the presence of concomitant medications which are known metabo

15、lic substrates, inhibitors or inducers.The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy subjects. The pharmacokinetic parameters of anidulafungin estimated using population pharmacokinetic modeling following IV administration of a main

16、tenance dose of 50 mg/day or 100 mg/day (following a loading dose) are presented in Table 2.Table 2. Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of Anidulafungin in Patients with Fungal Infections Estimated Using Population Pharmacokinetic Modeling

17、PK ParameterAnidulafungin IV Dosing Regimen (LD/MD, mg)100/50200/100All the parameters were estimated by population modeling using a two-compartment model with first order elimination; AUCss, Cmax,ssand Cmin,ss(steady state trough plasma concentration) were estimated using individual PK parameters a

18、nd infusion rate of 1 mg/min to administer recommended doses of 50 and 100 mg/day.LD/MD: loading dose/daily maintenance doset1/2, is the predominant elimination half-life that characterizes the majority of the concentration-time profile.Cmax, ssmg/L4.2 (22.4)7.2 (23.3)Cmin, ssmg/L1.6 (42.1)3.3 (41.8

19、)AUCssmgh/L55.2 (32.5)110.3 (32.5)CL L/h1.0 (33.5)t1/2, h26.5 (28.5)GenderDosage adjustments are not required based on gender. Plasma concentrations of anidulafungin in healthy men and women were similar. In multiple-dose patient studies, drug clearance was slightly faster (approximately 22%) in men

20、.GeriatricDosage adjustments are not required for geriatric patients. The population pharmacokinetic analysis showed that median clearance differed slightly between the elderly group (patients 65, median CL = 1.07 L/h) and the non-elderly group (patients 65, median CL = 1.22 L/h) and the range of cl

21、earance was similar.RaceDosage adjustments are not required based on race. Anidulafungin pharmacokinetics were similar among Whites, Blacks, Asians, and Hispanics.HIV StatusDosage adjustments are not required based on HIV status, irrespective of concomitant anti-retroviral therapy.Hepatic Insufficie

22、ncyDosage adjustments are not required on the basis of mild, moderate or severe hepatic insufficiency. Anidulafungin is not hepatically metabolized. Anidulafungin pharmacokinetics were examined in subjects with Child-Pugh class A, B or C hepatic insufficiency. Anidulafungin concentrations were not i

23、ncreased in subjects with any degree of hepatic insufficiency. Though a slight decrease in AUC was observed in patients with Child-Pugh C hepatic insufficiency, it was within the range of population estimates noted for healthy subjects.Renal InsufficiencyDosage adjustments are not required for patie

24、nts with any degree of renal insufficiency including those on hemodialysis. Anidulafungin has negligible renal clearance. In a clinical study of subjects with mild, moderate, severe or end stage (dialysis-dependent) renal insufficiency, anidulafungin pharmacokinetics were similar to those observed i

25、n subjects with normal renal function. Anidulafungin is not dialyzable and may be administered without regard to the timing of hemodialysis.PediatricThe pharmacokinetics of anidulafungin after daily doses were investigated in immunocompromised pediatric (2 through 11 years) and adolescent (12 throug

26、h 17 years) patients with neutropenia. The steady state was achieved on the first day after administration of the loading dose (twice the maintenance dose), and the Cmaxand AUCssincreased in a dose-proportional manner. Concentrations and exposures following administration of maintenance doses of 0.7

27、5 and 1.5 mg/kg/day in this population were similar to those observed in adults following maintenance doses of 50 and 100 mg/day, respectively (as shown in Table 3) (seePRECAUTIONS, Pediatric Use).Table 3. Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of Anidulafungin Once Daily in Pediatric SubjectsPK ParameterAnidulafungin IV Dosing Regimen(LD/MD, mg/kg)1.5/0.753.0/1.5Data were collected on Day 5LD/MD: loading dose/daily maintenan