10注射用阿尼芬净.docx

10注射用阿尼芬净.docx

《10注射用阿尼芬净.docx》由会员分享，可在线阅读，更多相关《10注射用阿尼芬净.docx（21页珍藏版）》请在冰豆网上搜索。

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StevenGalson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Eraxis，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由纽约州的Pfizer公司生产。

ERAXIS-anidulafungin injection,powder,lyophilized,forsolution  

Roerig 

ERAXIS™（anidulafungin）FORINJECTION 

[INTRAVENOUSINFUSION,DILUTEDWITHSTERILEWATERFORINJECTION]（notforIVBolusInjection）

DESCRIPTION

ERAXISforInjectionisasterile,lyophilizedproductforintravenous（IV）infusionthatcontainsanidulafungin.ERAXIS（anidulafungin）isasemi-syntheticlipopeptidesynthesizedfromafermentationproductof Aspergillusnidulans.Anidulafunginisanechinocandin,aclassofantifungaldrugsthatinhibitsthesynthesisof1,3-β-D-glucan,anessentialcomponentoffungalcellwalls.

ERAXIS（anidulafungin）is1-[（4R,5R）-4,5-dihydroxy-N2-[[4"-（pentyloxy）[1,1':

4',1"-terphenyl]-4-yl]carbonyl]-L-ornithine]echinocandinB. Anidulafunginisawhitetooff-whitepowderthatispracticallyinsolubleinwaterandslightlysolubleinethanol.Inadditiontotheactiveingredient,anidulafungin,ERAXISforInjectioncontainsthefollowinginactiveingredients:

50mg/vial -fructose（50mg）,mannitol（250mg）,polysorbate80（125mg）,tartaricacid（5.6mg）,andsodiumhydroxideand/orhydrochloricacidforpHadjustment.

100mg/vial -fructose（100mg）,mannitol（500mg）,polysorbate80（250mg）,tartaricacid（11.2mg）,andsodiumhydroxideand/orhydrochloricacidforpHadjustment.

TheempiricalformulaofanidulafunginisC58H73N7O17 andtheformulaweightis1140.3.

Thestructuralformulais:

Priortoadministration,ERAXISforInjectionrequiresreconstitutionwithsterileWaterforInjectionandsubsequentdilutionwitheither5%DextroseInjection,USPor0.9%SodiumChlorideInjection,USP（normalsaline）.

DONOTdilutewithothersolutionsorco-infusewithothermedicationsorelectrolytes（see DOSAGEANDADMINISTRATION）.

CLINICALPHARMACOLOGY

Pharmacokinetics

ThepharmacokineticsofanidulafunginfollowingIVadministrationhavebeencharacterizedinhealthysubjects,specialpopulationsandpatients.Systemicexposuresofanidulafunginaredose-proportionalandhavelowintersubjectvariability（coefficientofvariation<25%）asshowninTable1.Thesteadystatewasachievedonthefirstdayafteraloadingdose（twicethedailymaintenancedose）andtheestimatedplasmaaccumulationfactoratsteadystateisapproximately2.

Table1.Mean（%CV）SteadyStatePharmacokineticParametersofAnidulafunginFollowingIVAdministrationofAnidulafunginOnceDailyfor10DaysinHealthyAdultSubjects

AnidulafunginIVDosingRegimen（LD/MD,mg）

PKParameter

70/35 , 

（N=6）

200/100

（N=10）

260/130 , 

（N =10）

Cmax,ss =thesteadystatepeakconcentration

AUCss =thesteadystateareaunderconcentrationvs.timecurve

CL=clearance

t1/2 =theterminaleliminationhalf-life

LD/MD:

loadingdose/maintenancedoseoncedaily

Parameterswereobtainedfromseparatestudies

DatawerecollectedonDay7

Safetyandefficacyofthesedoseshasnotbeenestablished

SeeOVERDOSAGE

Cmax,ss [mg/L]

3.55（13.2）

8.6（16.2）

10.9（11.7）

AUCss [mg∙h/L]

42.3（14.5）

111.8（24.9）

168.9（10.8）

CL[L/h]

0.84（13.5）

0.94（24.0）

0.78（11.3）

t1/2 [h]

43.2（17.7）

52.0（11.7）

50.3（9.7）

Theclearanceofanidulafunginisabout1L/handanidulafunginhasaterminaleliminationhalf-lifeof40–50hours.

Distribution

ThepharmacokineticsofanidulafunginfollowingIVadministrationarecharacterizedbyashortdistributionhalf-life（0.5–1hour）andavolumeofdistributionof30–50Lthatissimilartototalbodyfluidvolume.Anidulafunginisextensivelybound（>99%）tohumanplasmaproteins.

Metabolism

Hepaticmetabolismofanidulafunginhasnotbeenobserved.Anidulafunginisnotaclinicallyrelevantsubstrate,inducer,orinhibitorofcytochromeP450（CYP450）isoenzymes.ItisunlikelythatanidulafunginwillhaveclinicallyrelevanteffectsonthemetabolismofdrugsmetabolizedbyCYP450isoenzymes.

AnidulafunginundergoesslowchemicaldegradationatphysiologictemperatureandpHtoaring-openedpeptidethatlacksantifungalactivity.The invitro degradationhalf-lifeofanidulafunginunderphysiologicconditionsisabout24hours. Invivo,thering-openedproductissubsequentlyconvertedtopeptidicdegradantsandeliminated.

Excretion

Inasingle-doseclinicalstudy,radiolabeled（14C）anidulafunginwasadministeredtohealthysubjects.Approximately30%oftheadministeredradioactivedosewaseliminatedinthefecesover9days,ofwhichlessthan10%wasintactdrug.Lessthan1%oftheadministeredradioactivedosewasexcretedintheurine.Anidulafunginconcentrationsfellbelowthelowerlimitsofquantitation6dayspost-dose.Negligibleamountsofdrug-derivedradioactivitywererecoveredinblood,urine,andfeces8weekspost-dose.

SpecialPopulations

Patientswithfungalinfections

PopulationpharmacokineticanalysesfromfourPhase2/3clinicalstudiesincluding107maleand118femalepatientswithfungalinfectionsshowedthatthepharmacokineticparametersofanidulafunginarenotaffectedbyage,race,orthepresenceofconcomitantmedicationswhichareknownmetabolicsubstrates,inhibitorsorinducers.

Thepharmacokineticsofanidulafungininpatientswithfungalinfectionsaresimilartothoseobservedinhealthysubjects.ThepharmacokineticparametersofanidulafunginestimatedusingpopulationpharmacokineticmodelingfollowingIVadministrationofamaintenancedoseof50mg/dayor100mg/day（followingaloadingdose）arepresentedinTable2.

Table2.Mean（%CV）SteadyStatePharmacokineticParametersofAnidulafunginFollowingIVAdministrationofAnidulafungininPatientswithFungalInfectionsEstimatedUsingPopulationPharmacokineticModeling

PKParameter

AnidulafunginIVDosingRegimen（LD/MD,mg）

100/50

200/100

Alltheparameterswereestimatedbypopulationmodelingusingatwo-compartmentmodelwithfirstorderelimination;AUCss,Cmax,ss andCmin,ss （steadystatetroughplasmaconcentration）wereestimatedusingindividualPKparametersandinfusionrateof1mg/mintoadministerrecommendeddosesof50and100mg/day.

LD/MD:

loadingdose/dailymaintenancedose

t1/2,β isthepredominanteliminationhalf-lifethatcharacterizesthemajorityoftheconcentration-timeprofile.

Cmax,ss [mg/L]

4.2（22.4）

7.2（23.3）

Cmin,ss [mg/L]

1.6（42.1）

3.3（41.8）

AUCss [mg∙h/L]

55.2（32.5）

110.3（32.5）

CL[L/h]

1.0（33.5）

t1/2,β [h]

26.5（28.5）

Gender

Dosageadjustmentsarenotrequiredbasedongender.Plasmaconcentrationsofanidulafungininhealthymenandwomenweresimilar.Inmultiple-dosepatientstudies,drugclearancewasslightlyfaster（approximately22%）inmen.

Geriatric

Dosageadjustmentsarenotrequiredforgeriatricpatients.Thepopulationpharmacokineticanalysisshowedthatmedianclearancedifferedslightlybetweentheelderlygroup（patients≥65,medianCL=1.07L/h）andthenon-elderlygroup（patients<65,medianCL=1.22L/h）andtherangeofclearancewassimilar.

Race

Dosageadjustmentsarenotrequiredbasedonrace.AnidulafunginpharmacokineticsweresimilaramongWhites,Blacks,Asians,andHispanics.

HIVStatus

DosageadjustmentsarenotrequiredbasedonHIVstatus,irrespectiveofconcomitantanti-retroviraltherapy.

HepaticInsufficiency

Dosageadjustmentsarenotrequiredonthebasisofmild,moderateorseverehepaticinsufficiency.Anidulafunginisnothepaticallymetabolized.AnidulafunginpharmacokineticswereexaminedinsubjectswithChild-PughclassA,BorChepaticinsufficiency.Anidulafunginconcentrationswerenotincreasedinsubjectswithanydegreeofhepaticinsufficiency.ThoughaslightdecreaseinAUCwasobservedinpatientswithChild-PughChepaticinsufficiency,itwaswithintherangeofpopulationestimatesnotedforhealthysubjects.

RenalInsufficiency

Dosageadjustmentsarenotrequiredforpatientswithanydegreeofrenalinsufficiencyincludingthoseonhemodialysis.Anidulafunginhasnegligiblerenalclearance.Inaclinicalstudyofsubjectswithmild,moderate,severeorendstage（dialysis-dependent）renalinsufficiency,anidulafunginpharmacokineticsweresimilartothoseobservedinsubjectswithnormalrenalfunction.Anidulafunginisnotdialyzableandmaybeadministeredwithoutregardtothetimingofhemodialysis.

Pediatric

Thepharmacokineticsofanidulafunginafterdailydoseswereinvestigatedinimmunocompromisedpediatric（2through11years）andadolescent（12through17years）patientswithneutropenia.Thesteadystatewasachievedonthefirstdayafteradministrationoftheloadingdose（twicethemaintenancedose）,andtheCmax andAUCss increasedinadose-proportionalmanner.Concentrationsandexposuresfollowingadministrationofmaintenancedosesof0.75and1.5mg/kg/dayinthispopulationweresimilartothoseobservedinadultsfollowingmaintenancedosesof50and100mg/day,respectively（asshowninTable3）（see PRECAUTIONS,PediatricUse）.

Table3.Mean（%CV）SteadyStatePharmacokineticParametersofAnidulafunginFollowingIVAdministrationofAnidulafunginOnceDailyinPediatricSubjects

PKParameter 

AnidulafunginIVDosingRegimen

（LD/MD,mg/kg）

1.5/0.75

3.0/1.5

DatawerecollectedonDay5

LD/MD:

loadingdose/dailymaintenan