braz j infect dis.2013;17(2):194–204
The
Brazilian
Journal
of
INFECTIOUS
DISEASES
w w w . e l s e v i e r . c o m / l o c a t e / b j i d
Review
article
Safety
aspects
of
protease
inhibitors
for
chronic
hepatitis
C:
adverse
events
and
drug-to-drug
interactions
Rosângela
Teixeira
a,b,∗,
Yone
de
Almeida
Nascimento
a,c,
Déborah
Crespo
daViralHepatitisClinic,InstitutoAlfadeGastroenterologia,HospitaldasClínicas,UniversidadeFederaldeMinasGerais,BeloHorizonte, MG,Brazil
bDepartmentofInternalMedicine,MedicalSchool,UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil cPharmaceuticalAttentionClinic,CentroUniversitárioNewtonPaiva,BeloHorizonte,MG,Brazil
dNúcleodeEstudosePesquisasemHepatologianaAmazônia,Belém,PA,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received31July2012 Accepted16October2012 Availableonline9March2013
Keywords: HepatitisC Proteaseinhibitors Adverseevents Druginteractions
a
b
s
t
r
a
c
t
ThestandardofcaretherapyofchronichepatitisCwiththecombinationofpegylated inter-feronandribavirinfor24or48weekswasaremarkableaccomplishmentofthepastdecade. However,sustainedvirologicalresponsesratesofabout80%(genotypes2–3)and50% (geno-type1)werenotsatisfactoryespeciallyforpatientsinfectedwithgenotype1.Important advancesinthebiologyofHCVhavemadepossiblethedevelopmentofthedirect-acting antiviralagentsboceprevirandtelaprevirwithsubstantialincreaseintheratesofsustained virologicalresponsewithshorterdurationoftherapyforalargenumberofpatients. How-ever,thecomplexityoftripletherapyishigherandseveralnewsideeffectsareexpected suggestinggreaterexpertiseinthepatient management.Anemiaanddisgeusiaare fre-quentwithboceprevirwhilecutaneousrash,rangingfrommildtosevere,isexpectedwith telaprevir.Higherriskofdrug–druginteractionsdemandfurtherclinicalconsiderationof thepreviouswell-knownadverseeventsofpegylatedinterferonandribavirin.Identification andpromptmanagementofthesepotentialnewproblemswithboceprevirandtelaprevir arecrucialinclinicalpracticeforoptimizingtreatmentandassuringsafetyoutcomesto HCV-genotype1patients.
©2013 ElsevierEditoraLtda.Allrightsreserved.
Introduction
Thestandardofcare(SOC)therapyofchronichepatitisCwith thecombinationofpegylatedinterferon(PegIFN)and ribavi-rin(RBV) for24 or48 weekswas aremarkabletherapeutic accomplishmentofthepastera.However,sustained virolo-gicalresponses(SVR)ratesofabout80%(genotypes2–3)and
∗ Correspondingauthorat:FaculdadedeMedicinadaUFMG,AvenidaAlfredoBalena,190/246,BeloHorizonte,MG30130-100,Brazil.
E-mailaddress:[email protected](R.Teixeira).
50%(genotype1)werenotsatisfactoryespeciallyforpatients infectedwithgenotype1.1Importantadvancesinthe
knowl-edgeofthe structureofHCVproteins,inconjunction with thedevelopmentofasubgenomicrepliconsystemandacell culturemodelthatenablesproductiveHCVinfection,2,3have
madepossiblethedevelopmentofnewdirect-acting antivi-ralagents(DAAs)withsubstantialincreaseofSVRrateswith shorterdurationoftherapyforalargenumberofpatients.4
1413-8670/$–seefrontmatter©2013 ElsevierEditoraLtda.Allrightsreserved.
brazj infect dis.2013;17(2):194–204
195
Recently,newtreatmentswith the proteaseinhibitors (PIs) boceprevir(BOC)andtelaprevir(TVR)havebroughtadditional chancesofcure.However,the complexity oftriple therapy ishigherandseveralnewsideeffectsandriskofdrug–drug interactions are anticipated. Identificationand appropriate managementofthesepotentialproblemsarecrucialinclinical practicefor optimizingtreatment and assuring safety out-comestoHCVpatients.Therefore,thepurposeofthispaperis toprovideanoverviewofclinicaldataregardingsafetyaspects ofPIsincludingadverseevents(AEs)anddrug-to-drug inter-actions.
Proteases
as
potential
targets
of
DAAs
EachstepofHCVlifecycleoffersapotentialtargetforDAA therapy.5TheNS2andNS3/4Aareviralpeptidasesinvolved
in the post-translational processing of HCV proteins. NS3 is a multifunctional viral protein containing a serine pro-tease domain in its N-terminal third (approximately 180 aminoacids)andahelicaseNTPasedomaininitsC-terminal two-third,andNS4A isacofactorofitsproteinase activity. NS3mustassemblewithitscofactorNS4AtocatalyzeHCV polyproteincleavage.
Preclinical data has demonstrated experimentally that HCVcontainingdefectiveNS3/4Aactivitycouldnotreplicate.6
This concept was the basis for the recent development oftwo first-generation NS3/4A anti-protease agents – TVR (Incivek®;VertexPharmaceuticals,Cambridge,MA,USA).7and
BOC(Victrelis®;Merck,Kenilworth,NY,USA),8 bothrecently
approvedto treat chronic hepatitis inEurope, USA and in Brazil.WhenusedincombinationwithPegIFNandRBV,these PIsimprove substantiallythe SVR ratesinboth treatment-naïvepatientsandinthosewithpreviousvirologicalfailure. Nevertheless, the addition of these new agents increased the complexity ofHCV treatment, asnew AEsand several drug–druginteractions,leadingtothediscontinuationofall antiviraltreatmentsin9–20%ofcases.9–13Inaddition,
resis-tancemutationsareanewmainconcern astheyare more likelytodevelopwithongoingexposuretoPIs.Thus,updated guidelinesofHCVtreatmenthavesetupstrictstoppingrules based on inadequate virological responses or severe side-effects.1,14
TVRisbioavailableandabsorbedinthesmallintestine.15
Foroptimalexposure,TVRmustbetakenwithfoodrichinfat. Systemicexposure(areaunderthecurve–AUC)isincreasedby 237%withastandardfatmeal(533kcaland21gfat)compared withthefastedstate.16Clinicaltrialshavealsodemonstrated
thatBOCAUCincreasedupto65%whentakenwithfood,but typeofmealandtimingarenotessential.17
Adverse
events
with
DAAs
ThetripletherapywithBOCorTVRhasdistinctiveAEs.The most importantside-effects associated with BOC are ane-mia,neutropeniaanddysgeusia(alteredsenseoftaste).With TVR,the AEs are slightly different from BOC as skin rash andanorectalsymptoms(discomfortandpruritus)aremore frequent.DosereductionsofIPsshouldnotbeusedinthe
managementofAEs,assuboptimaldosesofthesedrugswill promotetheemergenceofresistantHCVspeciesresultingin treatmentfailure.
AnemiawithPItreatment
Anemia,definedashemoglobinlevelsbelow10g/dL,isa rec-ognizedRBVrelatedeventwithconsiderableincreasedrateby theadditionofTVRorBOCtotheSOCHCVtreatment.In clin-icaltrials,tripletherapyresultedina20–26%increaseinthe rateofanemiawithPIscomparedtoSOC.14Thefrequencyof
anemiaishigherfortripletherapywithBOCascomparedto TVR(about50%and40%,respectively).Itseemstoresultfrom bone-marrowsuppressiveeffectandnothaemolysis.18
Theimpact ofanemia on the SVR ratewas distinct for thetwodrugsinclinicaltrials.Arecentpooledretrospective analysisoftwophase3studies(ADVANCEandILLUMINATE) evaluatedefficacyoutcomesofTVRinrelationtothe occur-renceofanemiain1239patients.19Thefrequencyofanemia
was41%and26%inpatientswithtripletherapywithTVRand SOC,respectively.SVRratesinpatientswithanemiawere74% and50%withtripletherapyandSOC,respectively.Conversely, SVR rates of patients without anemia were 73% and 41% withtripletherapyandSOCtreatment.Thesedatastrongly suggestedthatanemiahadnoeffectonSVR ratesin treat-mentnaïvepatients.Althoughanemiawasmorefrequentin patientswhoreceivedaTVR-basedregimenascomparedto patientsonSOCtreatment,thehemoglobinvaluesgradually improvedaftertheendofTVRatweek12andweresimilar tothoseonSOCbyweek20.19Inaddition,patientswith
TVR-basedtherapyandSOCwhodevelopedanemiahad72%and 58%ofRBVdosereductionduetoAEs,comparedto11%and 6%ofpatientswithoutanemia.SVRwasachievedby76%and 54% ofpatientswithRBVdosereductioninthe TVR-based therapyandSOC,respectively,comparedwith72%and41% ofpatientswithoutRBVdosereductioninTVR-basedtherapy andSOC,respectively.Thisdatasuggestedthatmanagement oftreatment-relatedanemiawithdosereductionofRBVdid notimpactSVRwithTVR-basedtherapy.19
The relationshipof anemia inBOC-based regimenwith SVRwasalsoinvestigatedinaretrospectiveanalysisof1097 treatment-naïveand403previous-treatmentfailurepatients includedinBOCtrials.Anemiaoccurredin49%andin29.7% ofpatientstreatedwithBOCregimenandSOC,respectively. ThemanagementofanemiaconsistedofEPOuseby78.5%of anemicpatientsonBOCregimensand29%ofthosetreated with SOC. In contrast to that observed in TVR trials, the SVRratewashigherinpatientswhodevelopedanemia com-paredtopatientswithoutanemiainbothnaïveorexperienced patients.19However,sinceabout80%ofanemicpatientstook
EPOinBOCtrials,therelationshipofSVRandreductionofRBV, anemiaandEPOusehasnotbeencompletelyestablishedwith TVRregimenssofar.
According to the recent UK guidelines for the use of the PIs in HCV treatment14 management of anemia
(Hb<10g/dL)andsignificantneutropenia(absoluteneutrophil count<750/mm3)shouldbeconductedasfollows:(a)RBVdose
shouldbestartedatfulltreatmentdoseanddosereduction institutedforanemiaatdecrementsof200g;(b)reductionin doseofIFN,ifbonemarrowsuppressionisevident;(c)EPO
196
braz j infect dis.2013;17(2):194–204administrationmaybeconsideredanduseduntilHb>12g/dL; supportivetreatmentwithbloodtransfusionshouldbe con-sideredinextremecircumstancesandsignificantneutropenia should be managed according to current practice for SOC treatment.Inaddition,considerationshouldbegiventodose reductionofPegIFN.Importantly,thedose ofPIshould not bereducedformanagingneutropeniaorbonemarrow sup-pression.Ifrequiredduetotheseverityofneutropenia,thePI shouldbestoppedcompletely.
DermatologicaleventsduringPItreatment
ThetypicaldermatologicalreactionswithSOCconsistof gen-eralizedpruritusandskinxerosis,witheczematiformlesions accentuatedbyerythematouspapulesandmicrovesiclesthat areoftenexcoriated,withpredominanceontheextremities andtruncalskinsitesexposedtofriction.20
UseofDAAsresultsinadditionalskindisorders.Higher frequencyandseverityofdermatologicalreactionshavebeen reportedwithTVR21–23andinfrequentlywithBOC,24,25aspart
oftripletherapyregimens.Thisfactisespeciallyimportantin clinicalpracticeasextrapatientmanagementconsiderations arerequiredbyHCV-treatingphysicians.
A pooled analysis of the dermatological safety profile among1346patientswhoreceivedatleastonedoseofTVRand 764patientswhoreceivedatleastonedoseofplaceboinfive placebo-controlledphaseII/IIItrialsofTVR,9,10,12,22rashand
prurituswereobservedin55%and51%ofpatientstreatedwith TVR-basedregimencomparedto33%and26%withplacebo.
InTVRtrials,rasheventsweregradedbyseverityintothree grades21,22 (Table1).Morethan90%ofrasheventsrelatedto
TVRwereGrade1or2(mild/moderate)anddidnotprogress. TheextentofrashinTVR clinical trialsgrades1, 2,and 3 were37%,14%and5%,respectively.In92%ofpatientswith rash,no progressiontoa moreseveregradewasobserved.
Approximately6%ofallpatientsrequireddiscontinuationof TVRasaresultofskinlesionsthatresolvedwith discontinua-tionofthedrug.About50%ofallrasheventsstartedduringthe firstfourweeksofTVRuse,withtheremaining50%starting untilweek12.Themediantimetoonsetofrashofanygrade was25days(rangingfrom1to350days),suggestingthatitcan occuratanytimeduringtreatment.26AfterstoppingTVRat
week12,theincidenceofrashwascomparablebetweenTVR andplacebo-treatedpatients.27
Basedonasystematicretrospectiveassessmentreviewof photographsandbiopsiesofallrasheventsreportedinPhase IIITVR trials,theexpertpanelofdermatologistsconcluded thatthevisualappearanceandhistopathologyofrash asso-ciatedwithTVRarecomparabletotherashassociatedwith SOC,thoughTVR-associatedrasheswereofincreasedseverity andextent,whichmayoccuranytimeduringtreatment,and resolveoverweeksafterdiscontinuationofTVR.Inaddition, thebiopsieswerenotsuggestiveofvasculitis.26
There is no worldwide consensus on the definition of severecutaneousadversereaction(SCAR);however,the con-sensuspaneldefinedthatdermatologicalconditionsthatare life-threatening and frequently attributed to drug therapy werereportedasSCAR,includingStevens–Johnsonsyndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalizedexanthematouspustulosis(AGEP).Clinical inves-tigatorsintheTVRdevelopmentprogramreportedsixsubjects withSCARandthepanelassessedfourassuspectedSCAR(one definitiveSJS,onedefinitiveDRESSandtwopossibleDRESS cases).Nine outof11 suspectedDRESScasesdidnothave systemic organ involvement while organ involvement was unconfirmedintwo(FDAaccessed12March,2012).SJSand TENareveryacuteevents,withamortalityrateof25% dur-inghospitalization.DRESSismoreprogressiveandlesssevere, withmortalityratearound10%.28
Table1–GradingandmanagementofTelaprevirrashseverity.a
Grade Description Management
Grade1–mild Localizedskineruptionand/orlimitedskineruptionwithorwithout associatedpruritus
Telaprevirinterruptiongenerallyisnot necessary
Grade2–moderate Diffuseskineruptioninvolvingupto50%ofbodysurfaceareawithor withoutsuperficialskinpeeling,pruritus,ormucousmembrane involvementwithnoulceration
Telaprevirinterruptiongenerallyisnot necessary
•Forprogressiveeruptiontelaprevir shouldbediscontinuedfirst.
•Considerinterruptingribavirinand/or peginterferonifnoimprovementin eruptionwithin7daysofstopping telaprevir,orearlierifrashworsens. Grade3–severe GeneralizedrashinvolvingEITHER>50%ofbodysurfaceareaORrash
presentingwithanyofthefollowingcharacteristics: •Vesiclesorbullae
•Superficialulcerationofmucousmembranes •Epidermaldetachment
•Typicaloratypicaltargetlesions
•Palpablepurpura/non-blanchingerythema
Telaprevirmustbestoppedimmediately •Interruptribavirinand/orpeginterferon ifnoimprovementsinrashwith7daysof stoppingtelaprevir,orearlierifrash worsens.
Life-threateningor systemic reactions
Stevens–Johnsonsyndrome(SJS),toxicepidermalnecrolysis(TEN), drugreactionwitheosinophiliaandsystemicsymptoms(DRESS),rash thatrequirestherapywithsystemiccorticosteroids
Permanentdiscontinuationofall treatment
brazj infect dis.2013;17(2):194–204
197
Fig.1–Practicalschemefordeterminingpercentagesof bodysurfacearea(BSA)affectedbyskinreactionsinadults.
Adult Surface% Arm 9 Head 9 Neck 1 Leg 18 Face/anteriortrunk 18 Face/posteriortrunk 18
ThemechanismofTVR-relatedrashremainsunknownand nopredictors havebeen identified.An analysisofmultiple HLAallelesperformedtodetermineifthegeneticbackground mayincreaseordecreasetheriskofdevelopingarashduring TVR-basedregimendidnotrevealastrongassociationofany HLAallelewithrash.26
TheseconddermatologicalAEsassociatedwithTVRwas pruritus,ingeneralassociatedwithrashbutcouldalsobeseen withoutit.
Treatmentandmanagementofrash
Therecommendationsforgradingandmonitoringthe derma-tologicalreactionsandfordiscontinuationofTVR,PegIFNand RBVhavebeenbasedontheextensionandfeaturesof derma-tologicalreactions.Anestimateofbodysurfacearea(BSA)has beenusedasanindicatoroftheseverityofadermatological reaction(Fig.1).
OneimportantpointtoHCV-treatingphysiciansistobe abletodistinguishbetweenusualdermatitisandSCAR.The mostfrequentTVR-dermatitisisasingleentitythatgenerally beginsduringthefirstfourweeksoftherapy,butcanoccur atany time during treatment. Thereaction is an eczema-tousdermatitissimilartothatobservedwithSOC,butismore frequentandseverewithTVR-regimen.Typicalrashinclude pruritus and skin dryness and is stable. The continuation ofthe triple therapyispossible inGrades1and 2or even
Table2–Biologicalsignsandsymptomstodistinguish amongthemostseveretelaprevir-relatedcutaneous adversereactions(SCARS):drugreactionwith eosinophiliaandsystemicsymptoms(DRESS), Stevens–Johnsonsyndrome(SJS)andtoxicepidermal necrolysis(TEN).26
DRESS SJSorTEN
Onsetfrom5–10weeksafterdrug use
Rapidlyprogressive exanthema Rapidlyprogressiveexanthemain
>50%ofBSAa
Skinpain
Presenceofbullaeandvesicles Mucosalinvolvementat morethantwosites Prolongedfeveringeneral>38.5◦C Blistersorepidermal
detachment
Facialedema Atypicaltargetlesions
Enlargedlymphnodes Eosinophilia>10% Atypicallymphocytes
RisesinALT,AP(≥2timesupper normallimit)
Riseincreatinine(≥150%basal level)
a BSA:bodysurfacearea.
in Grade3withappropriatemanagement. However,in the rareSCARpresentation,potentiallylife-threateningif unrec-ognizedorunmanaged,immediatetreatmentdiscontinuation ismandatory.27
Accordingtosomeauthors27 somecasesofGrade3
der-matitis reaction affecting more than 50% of body surface but withno signsofSJS, TEN,DRESS, EMor AGEP,maybe manageableusingtopicalcorticosteroidswithouttreatment discontinuation.Insuchcases,hospitalizationisrequiredto close follow up and intervention in case of signs of pro-gression. Experienceddermatologistsshouldberesponsible forpatientmanagement. ThemaintenanceofPeg/RBVwas allowedinPhaseIIIstudiesofTVRafterthecessationofthis drug,tokeepthechanceofSVRwhileminimizingtheriskof DRESSorSJS.However,thelesscommonbutpotentially life-threateningreactionssuchasSJS,TENandDRESSrequired promptcessationofalldrugs.27Differentialdiagnosisbased
on biologicalsigns andsymptoms hasbeen suggested27 to
helpphysiciansdistinguishingbetweenTVR-related dermati-tis,whereantiviraltreatmentcanbecontinuedandsupportive treatmentgiven,andthelesscommonbutpotentiallyharmful SJSandDRESSreactions(Table2).
Inthecaseofrashgrade1or2,patientscanbenefitfrom skincarethatmaylimitsymptomsandallowantiviraltherapy tobecontinuedforaslongaspossibleoptimizingthe likeli-hoodforviralclearancewithTVR-basedtherapy.Goodskin carepracticesincludeprophylacticapplicationofemollient creamsandlipid-richlotions,ratherthanaqueouslotionsor ointmentsaftershowerorbath,whentheskinisstillhydrated. ItisimportanttokeepinmindthatTVRdiscontinuationin anycaseisdefinitive.Hence,themajoraimisnotto underesti-mateanyskinreactions,butalsotoavoidstoppingtreatment ifunnecessary.Thefinaldecisionmighttakeinaccountthe clinicalevaluationofadermatologist.
198
braz j infect dis.2013;17(2):194–204GastrointestinaldisorderswithBOCandTVR
Dysgeusia, usually a metallic taste, has an increased fre-quency inpatients receiving BOC and PegIFN/RBV (35% in SPRINT-1and-2;44%inRESPOND-2)comparedwithpatients receivingSOCalone(16%inSPRINT-1and-2;11%in RESPOND-2).11,13,25 AEs such as dry mouth, nausea, vomiting and
diarrheawereobservedwithBOCregimen,butdiarrheaand vomitingweremorecommoninpatientswithTVRregimen comparedtoSOC.
Anorectal symptoms occurred more frequently in TVR (26.2%) compared with control arms (5.4%) in TVR trials.10,12,22 The symptoms included hemorrhoids, anal
pruritus/discomfortorrectalburningusuallywithinthefirst twoweeksofTVRtherapy.Mosteventsweremild/moderate and rarely lead to discontinuation of HCV treatment. All symptomswereresolvedafterinterruptionofTVR.
The mechanisms to explain anorectal symptoms are unknown and no association with dermatological AEs has been evident. Patients should undergo anal examination pre-treatment in order to exclude previous local lesions. Symptomaticand non-specificcare may be considered for managinganorectal disorders, including topical corticoste-roidsandsystemicantihistamineincaseofpruritus.
Drug
interactions
with
BOC
and
TVR
TheadequateconcentrationofDAAsiscriticaltoHCV treat-mentsuccess. Druginteractionswith potentialtodecrease DAAs levels can result in lower efficacy and development ofdrugresistance.18,19,30 Incontrast,drug–druginteractions
that increase DAAs levels and exposure increase also the riskofAEs.Hence,theeffectivemanagement ofdrug–drug interactions is essential to optimize the benefits of treat-mentofpatientsinfectedwithHCVgenotype1.18Therefore,
physiciansshouldexplorecarefullythehistoryofdrugsuse prescribed or not and also plant-based agents. Physicians arealsoadvisedtoconsulttheavailabledatabasesregarding potentialdrug–druginteractions.
Theknowledge ofthe main mechanisms ofdrug inter-actions contributes to assess the risk and to implement appropriateactionsinordertoavoidtheiroccurrence.
Pharmacokinetic interactions involving changes in metabolism are the most important drug interactions. TheCYPenzymesareresponsibleforthemostpartofdrug metabolism. As a consequence, the most frequent and importantmechanismfordruginteractionsisCYPinhibition, withpotential topromotehigh levels ofdrugs andrelated toxicity.29,30 Todate,mostdruginteractionswithnewDAAs
originate from in vitro studies, case reports and clinical suspicion.Someinteractionsaretheoretical.
About60%ofmedicationsaremetabolizedbyCYP3A,thus severaldruginteractions mustbeconsideredwithBOCand TVRastheyarebothsubstratesandinhibitorsofCYP3A29,31
(Table3).
BOCismetabolizedbyaldoketoreductase(AKR)1C2 and 1C3and,toalesserextent,byoxidativemetabolismmediated byCYP3A4/5.AsBOCutilizesmultipleroutesofmetabolism, itislesspronetodruginteractions.31,32Theprimaryrouteof
metabolismofTVRisCYP3A4.Thisdrughaslowpotentialto induceCYP2C,3A,or1A.
InadditiontointeractionsmediatedbyCYP3A,TVR and BOC are susceptibletointeractions membrane transporter-mediated. Both agents are substrates and inhibitors of P-glycoprotein(P-gp) andcaninhibitorsaturatethis trans-porter,thusincreasingtheconcentrationsofsubstrates.29,31,32
Table4liststhemainsubstrates,inhibitorsandinducersofthe
CYP3A4.
Antiretroviraldrugs
SeveralcommonlyusedantiretroviraldrugstotreatHIVaffect theCYP3Ametabolicpathwayorareitssubstrates.31,33 Con-comitant administration of TVR and efavirenz resulted in reduced steady-state exposure of both drugs. However, by increasingtheTVRdosefrom800mgto1125mgevery8h(i.e. 50%),TVRexposurecanbeatleastpartiallycompensated.This strategy hasbeensuccessfullyused inaphase2astudyin HIV/HCVcoinfectedpatients.29,32
Ritonavirisusedatalowdose(100mgonceortwicedaily) toinhibitCYP3AmetabolismofotherHIVPIsandenhanceits levels.ThisstrategywasinvestigatedforbothBOCandTVR. However,ritonavir-boostingdoesnotappeartodecreaseTVR orBOCpillburdenordosingfrequency.29,31
Inclinical studies,administrationofTVRwith ritonavir-boosted HIV PIs atazanavir, darunavir, fosamprenavir and lopinavirdecreasedtheexposuretoTVR.Thiseffectwasnot predicted,asHIVPIsboostedwithritonavirinhibitCYP3A4 andthereforemaybeexpectedtoincreaseTVRlevels.29,32
Ritonavir-boosted atazanavir is the combination less affectedandisbeingstudiedinHIV/HCVcoinfectedpatients withoutdoseadjustmentofeitheragent.29,31
Raltegravirisanattractiveagentforuseinthetreatment ofHIVintheHIV/HCVcoinfectedpatientsasitsprimaryroute ofmetabolismisglucuronidationandit doesnotinhibitor induce CYPenzymes.Incombination with TVR,raltegravir AUCwasincreased,presumablyduetoTVRinhibitionof P-gp.Raltegravirhasawidetherapeuticindexandthisincrease inAUCisnotexpectedtohaveclinicalrelevance.29Therisk
ofanemiaishigherifzidovudineisusedwithBOCorTVR, particularlyincombinationwithRBV.32,33
Immunosuppressants
It is critical to determine the safest and most effective dosesofTVRorBOCtoHCV-transplantedpatients.However, mostcommonlyusedimmunosupressorsaffecttheCYP3A metabolicpathwayorarethemselvessubstrates.Theseagents havenarrowtherapeuticwindowsandtheimpactof introduc-inganagentwithpotentialinteractionsuchasBOCorTVR, may resultin serious AEs.31 Preliminary data suggest that
cyclosporinemaybepreferredtotacrolimusinthesettingof TVRorBOC-basedHCVtreatment,butitmaystillbepossible tousetacrolimusinaverycontrolledmanner.29
Sirolimusisexpectedtobehavesimilarlytotacrolimus,but druginteractionwithDAAshasnotbeenstudiedyet.29The
longerhalf-lifeofsirolimus(60h),togetherwiththesignificant anemiacausedbyBOCorTVRcouldprovideadditivetoxicity
b r a z j i n f e c t d i s . 2 0 1 3; 1 7(2) :194–204
199
Table3–Druginteractionswithboceprevir(BOC)andtelaprevir(TVR). Co-administered
drug
Pharmacokineticparameters Comments/recommendations
Boceprevir Telaprevir Co-administereddrug
AUC Cmax AUC Cmax AUC Cmax
Antiretroviraldrugs
Efavirez ↓19% ↓8% ↓26% ↓9% ↑20%(BOC) ↑11%(BOC) TVRandBOC:combinationshouldbeavoided;thismayresultinlossof
therapeuticeffect.
Tenofovir ↑8% ↑5% – – ↑5%(BOC) ↑30%(TVR) ↑32%;(BOC)↑30%(TVR) TVRandBOC:nodosageadjustmentnecessary;clinicalandlaboratory
monitoringisrecommended;discontinuetenofovirifadverseeffectsoccur. Proteaseinhibitor
Ritonavir(R) ↓19% ↓27% ↓24% ↓15% – – TVR:nodosageadjustmentnecessary(withatazanavir,raltegraviror
ritonavir).
Lopinavir+R – – ↓32–54% ↓53% ↑(Minimal) – TVR:combinationshouldbeavoided(withlopinavir,fosempraviror
darunavir)duetoHCV/HIVtreatmentfailure. BOC:effectsunknown.
Fosempravir+R – – ↓32% ↓33% ↓47–49%(TVR) ↓35–40%(TVR)
Darunavir+R – – ↓35% ↓36% ↓40–51%(TVR) ↓40–47%(TVR)
Atazanavir+R – – ↓20% ↓21% ↑17%(TVR) –
Raltegravir – – – – ↑31%(TVR) –
Antimicrobials
Rifampin – – ↓92% ↓86% – – TVRandBOC:combinationshouldbeavoided.
Rifabutin TVRandBOC:combinationshouldbeavoided.
Clarithromycin, erythromycin telithromycin
↑ ↑ ↑ TVR:cautioniswarrantedandclinicalmonitoringisrecommended.
BOC:nodosageadjustmentnecessary.
Antifungals
Ketoconazole ↑131% ↑41% ↑62% ↑24% ↑46–125%(TVR) ↑23–75%(TVR) BOCandTVR:dosesofketoconazoleshouldnotexceed200mg/day.
Itraconazole – – – – – – BOCandTVR:dosesofitraconazoleshouldnotexceed200mg/day.
Voriconazole – – – – – – Theinteractioncannotbepredicted.
Contraceptives
Drospirenone – – – – ↑99%(BOC) ↑57%(BOC) BOC:combinationshouldbeavoided.
Ethinylestradiol(EE) – – – – ↓25%(BOTH) – TVRandBOC:non-hormonalcontraceptionshouldbeused.
Norethindrone – – – – ↓11%(TVR) – TVR:reducesnorethindroneslightly.
Anxiolytics/sleepaids
Midazolamoral – – – – ↑796%(TVR)↑430%(BOC) ↑177(BOC) 186%(TVR) TVRandBOC:contraindicated.
Midazolam intravenous
↑240%(TVR) ↑2%(TVR) TVR:contraindicated;BOC:halvingthedoseofintravenousmidazolamcould
beconsideredwithmonitoringfortoxiceffects.
Alprazolam – – – – ↑35%(TVR) – TVR:alowerdoseofintravenousalprazolamshouldbeconsidered;closely
monitorpatientforrespiratorydepressionandprolongedsedation.
Triazolam TVR:contraindicated(oralandintravenous);BOC:contraindicated(oral).
Zolpidem – – – – ↓42%(TVR) – TVR:ahigherdoseofzolpidemmayberequired;anydosageadjustments
madeduringconcomitantTVRtherapyshouldbere-adjustedfollowing completionofTVRtherapy.
200
b r a z j i n f e c t d i s . 2 0 1 3; 1 7(2) :194–204 –Table3(Continued) Co-administered drugPharmacokineticparameters Comments/recommendations
Boceprevir Telaprevir Co-administereddrug
AUC Cmax AUC Cmax AUC Cmax
Antidepressants
Escitalopram ↓35%(TVR);↓21%(BOC) ↓30%(TVR)
Immunosuppressants
Cyclosporine – – – – ↑364%(TRV) ↑32%(TRV) BOCandTVR:empiricallyreducingthecyclosporinedoseby75%,thenusing
therapeuticdrugmonitoringtofurtherrefinethecyclosporinedoseand frequency;TVR↑themeanhalflife(12hfrombaselineto53h).BOC:↑ cyclosporineAUC(2.7-foldfrombaseline).
Tacrolimus – – – – ↑6900%(TRV) ↑835%(TRV) TVRandBOC:significantdosereductionsandprolongationofdosinginterval
maybeneeded;closemonitoringrecommended;TVR↑themeanhalflife (40hfrombaselineto196h).BOC:↑tacrolimusAUC(17.1-foldfrombaseline).
Sirolimus – – – – ↑ ↑ Sirolimusisexpectedtobehavesimilarlytotacrolimus.
Dexamethasone, Prednisolone, methyl-prednisolone
↓ ↓ – – TVRandBOC:co-administrationwithCYP3A4/5inducersmaydecrease
antiretroviralslevels;ifpossible,thecombinationshouldbeavoided;used withcautionifnecessary.
Budesonide, Fluticasone(inhaled)
– – – – ↑ – BOCandTVR:ifpossible,thecombinationshouldbeavoided;usedwith
cautionifnecessary;mayresultin↑plasmaconcentrationsofthesteroid, causingsignificantlyreducedserumcortisol.
Anticonvulsants
Carbamazepine ↓ – ↓ – ↑ – TVRandBOC:ifpossible,thecombinationshouldbeavoided;usedwith
cautionifnecessaryanddosetitrationisrecommended.Concentrationsof theanticonvulsantmaybealteredandconcentrationsofTVRandBOCmay bedecreased.
Phenobarbital ↓ – ↓ – ↑ –
Phenytoin ↓ – ↓ – ↑ –
Anti-psychotics – Therearereportsofanti-psychotictoxicitywhencombinedwithCYP3A
inhibitor.
Aripiprazole – – – – ↑ – TRVandBOC:dosageofaripiprazoleshouldbeempiricallyreducedbyhalf
whenareinitiatedandtheanti-psychoticdosethentitratedtoeffect.
Quetiapine – – – – – – TRVandBOC:Ifpossible,quetiapineuseshouldbeavoided.
Clozapine – – – – – – TRVandBOC:monitorcarefullyforQTintervalprolongationanddiscontinue
clozapineiftheQTintervalexceeds500ms.Patientswhoexperience syncope,dizzinessorpalpitationsshouldhavefurtherevaluation,including cardiacmonitoring.
Pimozide – – – – – – TVRandBOC:contraindicated.
HMG-CoAreductaseinhibitors
Atorvastatin – – – – ↑688%(TVR) ↑960%(TVR) TVR:contraindicated;BOC:↑Cmaxby2.7-foldandAUCby2.3-fold;monitor
patientsforadverseeffects(myopathy/rhabdomyolysis,elevatedliver enzymes)andthelowestdoseshouldbeused(20mgatorvastatin).
Simvastatin – – – – ↑ ↑ TVR:contraindicated.
Lovastatin – – – – ↑ ↑ TVR:contraindicated.
Rosuvastatin – – – – TVRandBOC:couldbeconsideredforuseincombinationwithrosuvastatin;
b r a z j i n f e c t d i s . 2 0 1 3; 1 7(2) :194–204
201
–Table3(Continued) Co-administered drugPharmacokineticparameters Comments/recommendations
Boceprevir Telaprevir Co-administereddrug
AUC Cmax AUC Cmax AUC Cmax
AngiotensinIIreceptorblocker
Irbesartan,Losartan – – – – ↑ – TVRandBOC:dosereductionscouldbeconsidered.
-Blockers Carvedilol, Nabivolol
– – – – ↑ – TVRandBOC:dosereductionscouldbeconsidered.
Calciumchannelblockers
Felodipine, nifedipine, nicardipine, nisoldipine
– – – – – – TRVandBOC:clinicalmonitoringforadverseeffectsisrecommended
(headache,peripheraledema,hypotension,tachycardia).
Amlodipine – – – – ↑179%(TVR) ↑27%(TVR) TVR:dosereductionscouldbeconsideredinpatientsinitiatingantivirals;if
doseadjustmentsarerequired,returntonormalamlodipinedosingafter therapywithtelaprevirhasbeencompleted.
Verapamil,diltiazem – – – – ↑ ↑ TRV:cautionandclinicalmonitoringadvised.
Antiarrhythmics
Amiodarone, bepridil,quinidine, flecainide, propafenone
– – – – ↑ ↑ TVRandBOC:cautionandclinicalmonitoringisrecommended;potentialfor
seriousand/orlife-threateningadverseevents.
Otheragents
Digoxin – – – – ↑85%(TVR) ↑50%(TVR) TVRandBOC:initialdoseshouldbeusedwithtitrationandmonitoringof
serumdigoxinconcentrations.
Alfuzosin – – – – – – TVR:contraindicated;co-administrationmayresultinwhichmayresultin
hypotension. PDE-5inhibitors
(sildenafil,tadalafil, vardenafil)
– – – – ↑ – TVRandBOC:contraindicated(forpulmonaryarterialhypertension);lower
dosesshouldbeused;forerectiledysfunctionincreasedmonitoringfor adverseevents(hypotension,visualabnormalities,syncope,andpriapism).
Colchicine – – – – ↑ – TVRandBOC:areductionincolchicinedosageoraninterruptionof
colchicinetreatment(TVR)isrecommended;avoidco-administrationin renal/hepaticimpairment.Significantincreasesincolchicinelevelsexpected withstrongCYP3A4inhibitors;fatalcolchicinetoxicityreported.
Warfarin – – – – ↑or↓ – TVRandBOC:INRmustbemonitoredclosely.
Ergotalkaloids TVRandBOC:contraindicatedduetothepotentialforacuteergottoxicity
(e.g.,peripheralvasospasm,ischemiaoftheextremitiesand/orothertissues) Hypericum
perforatum
↓ – ↓ – – – TVRandBOC:contraindicated.
Adaptedfrom:(1)Wilby31;(2)Seden33;(3)Kiser29;(4)LiapakisandJacobson35;(5)Hézode18;(6)SedenandBack.32 (↑)increase;(↓)decrease;(–)noeffectorunknown.
202
b r a z j i n f e c t d i s . 2 0 1 3; 1 7(2) :194–204Table4–Mainsubstrates,inducersandinhibitorsofcytochromeP4503A4.
Substrates Inducers Inhibitors
Alfentanil Clarithromycin Ergotamine Indinavir Omeprazole Simvastatin Aminoglutethimide Amiodarone Nifedipine
Alfuzosin Clindamycin Erlotinib Isradipine Ondansetron Sirolimus Amprenavir Amprenavira Nilotinib
Aliskiren Clomipramine Erythromycin Itraconazole OralContraceptives Solifenacin Aprepitant Aprepitanta Norfloxacin
Almotriptan Clonazepam Escitalopram Ketoconazole Oxybutynin Sorafenib Carbamazepine Atazanavirb Pomegranate
Alprazolam Clopidogrel Esomeprazole Lapatinib Paclitaxel Sunitinib Dexamethasone Chloramphenicol Posaconazoleb
Amitriptyline Clozapine Estrogens,oral Lansoprazole Pantoprazole Tacrolimus Efavirenz Cimetidine Pazopanib
Amiodarone Cocaine Contraceptives Letrozole Pazopanib Tadalafil Ethosuximide Ciprofloxacin Prednisone
Amlodipine Colchicine Eszopiclone Levobupivacaine Pimozide Tamoxifen Etravirine Clarithromycinb Propoxyphene
Amprenavir Cyclobenzaprine Ethinylestradiol Lidocaine Pioglitazone Telithromycin Garlicsupplements Cyclosporine Quinine Aprepitant Cyclophosphamide Ethosuximide Lopinavir Prednisolone Temazepam Glucocorticoids Danazol Ranolazine
Asenapine Cyclosporine Etonogestrel Loratadine Prednisone Testosterone Glutethimide Delavirdine Ritonavirb
Atazanavir Dapsone Etoposide Losartan Progesterone/ Tiagabine Griseofulvin Diltiazema Saquinavirb
Atorvastatin Darifenacin Etravirine Lovastatin Progestins Tinidazole Modafinil Darunavir/ritonavirb Synercid
Beclomethasone Darunavir Exemestane Maraviroc Propafenone Tipranavir Nafcillin Dronedaronea Telithromycinb
Bepridil Dasatinib Everolimus Methadone Propoxyphene Tolterodine Nevirapine Erythromycina Tipranavir/ritonavirb
Bexarotene Delavirdine Felodipine Methylprednisolone Quetiapine Tolvaptan Oxcarbazepine Ethinylestradiol Verapamila
Bromocriptine Desogestrel Fentanyl Miconazole Quinidine Toremifene Phenobarbital Everolimus Voriconazoleb
Budesonide Dexamethasone Fesoterodine Midazolam Quinine Tramadol Phenytoin Fluconazolea Zafirlukast
Buprenorphine Dextromethorphan Fexofenadine Mifepristone Rabeprazole Trazodone Primidone Fluoxetine
Buspirone Diazepam Finasteride Mirtazapine Ramelteon Triazolam Rifabutin Fluvoxamine
Busulfan Dihydroergotamine Flutamide Modafinil Ranolazine Trimetrexate Rifampin Fosamprenavira
Cannabinoids Diltiazem Fluticasone Mometasone Repaglinide Valdecoxib Rifapentine Grapefruita
Caffeine Disopyramide Fluvestrant Montelukast Romidepsin Vardenafil Ritonavir Indinavirb
Carbamazepine Docetaxel Galantamine Nateglinide Rifabutin Verapamil St.John’swort Imatinib
Cevimeline Dofetilide Guanfacine Nefazodone Rifampin Vinblastine Isoniazid
Chlorpheniramine Dolasetron Haloperidol Nelfinavir Ritonavir Vincristine Itraconazoleb
Cilostazol Domperidone Hydrocodone Nevirapine Salmeterol Vinorelbine Ketoconazoleb
Ciclesonide(desciclesonide Donepezil Hydrocortisone Nicardipine Saquinavir Voriconazole Lapatinib
[activeMetabolite]) Doxorubicin Ifosfamide Nifedipine Saxagliptin (r)-warfarin Methylprednisolone
Cinacalcet Dronabinol Iloperidone Nilotinib Sertraline Zaleplon Mifepristone
Cisapride Dronedarone Imatinib Nimodipine Sibutramine Zileuton Nefazodoneb
Citalopram Dutasteride Imipramine Nisoldipine Sildenafil Ziprasidone Nelfinavirb
Efavirenz Ixabepilone Nitrendipine Silodosin Zolpidem Nicardipine
Eplerenone Norethindrone Zonisamide
Italicsdenotethosesubstrates,inhibitors,andinducersthathavebeeninvolvedinadruginteractionofclinicalrelevance,and/orareassociatedwithstrongdruginteractionwarningsor recommen-dationsforspecificintervention(i.e.,dosealteration,laboratorymonitoring,oravoidance).Formanymedications,strengthofinhibitioninvivoisundetermined.
a Moderateinhibitors(2-to<5-foldincreaseinexposure,or50–80%decreaseinclearanceofsubstrate). b Stronginhibitors(>5-foldincreaseinexposure,or>80%decreaseinclearanceofsubstrate).
brazj infect dis.2013;17(2):194–204
203
andmakeconcurrenttherapydifficulttomanageinclinical practice.31
HMG-CoAreductaseinhibitors
Simvastatin,atorvastatinandlovastatinarehighlydependent onCYP3Aforitsmetabolismandincreasingreportsalerttothe riskofmyopathyandrhabdomyolysisinpatientswithhigher concentrationsofsimvastatinandatorvastatincausedbydrug interactionswithapotentCYP3Ainhibitor.29,34
Pravastatin is metabolized by multiple pathways. The mechanism for the interaction of BOC with pravastatin is unclear, but may be related to BOC related inhibition of OATP1B1.29
RosuvastatinismetabolizedbyCYP2C9and2C19andcould beconsideredforuseincombinationwithBOCorTVR,butit stillneedstobeconfirmedasunexpectedincreasesin rosu-vastatinconcentrationshavebeen reportedincombination withseveralHIVPIs.29
Oralcontraceptives
RBVishighlyteratogenicandpreventionofpregnancyduring itsuseiscritical.Patientsareadvisedtouseatleasttwoforms ofbirthcontrolduringtreatmentwithPeg-IFN/RBVandforsix monthsthereafter.29,35
The combination of BOC and TVR and ethinylestradiol may decrease the plasma concentrations of the drug with potentialforfailureofbirthcontrol.Systemichormonal con-traceptionmust beaugmented bytwoalternative effective formsofcontraceptionandmayincludeintrauterinedevices and barrier methods during therapy and for six months following BOC therapy.36 BOC increases drospirenone
lev-els and high concentrations of this drug can theoretically causehyperkalemia.29Inaddition,basedonarecentreview
bytheFDA,drospirenone-containingbirthcontrolpillsmay be associated with higher risk for blood clots than other progestin-containingpills.34
Psychotropicmedications
Theselectiveserotoninreuptakeinhibitors(SSRIs)are gener-allythefirstlinetreatmentofdepressioninHCVpatientsdue totheirsafetyinoverdose andimprovedtolerability.There arenoobviousconcentration-effectdatafortheSSRIs,soit isunknownifreductionsinexposurescanbetranslatedin reducedabilitytocontroldepressivesymptoms.29
TherearenoformaldruginteractionstudiesbetweenTVR orBOCand antipsychotics,thus predictionsmustbemade based on knowledge of the clinical pharmacology of each agent.29
Midazolam is a selective CYP3A substrate. Flurazepam, quazepamandtriazolamarealsohighlydependentonCYP3A formetabolism and combination with TVR or BOCshould beavoided.29 Lorazepam and oxazepam are notconverted
into activemetabolite andare only conjugated,thusthese drugscouldbeconsideredforpatientsusingIPs.Trazodone isalsousedasasleepaid.WiththeHIVPIritonavir,trazodone exposuresareincreased,causingnausea,dizziness, hypoten-sionandsyncope.29
Cardiovasculardrugs
CYP enzymes are not involved in the metabolism of ACE inhibitors or diuretics. Among the beta blockers, only carvedilol andnabivololaremetabolizedtosomeextentby CYP3A4.ThereisacontributionofCYP3A4tothemetabolism ofangiotensin II receptorblockersirbesartanand losartan. ThecalciumchannelblockersarehighlydependentonCYP3A formetabolismandarethereforesusceptibletoincreasesin exposurewithBOCorTVR.29
BOCandTVRare bothsubstratesand inhibitorsofP-gp. Digoxinisnotmetabolized,butisaselectivesubstrateofP-gp. TVRcanincreasetheexposureofdigoxinanditwasthought toresultfrominhibitionorsaturationofP-gpinthegutrather thanatasystemiclevel.29,32
AmiodaroneisasubstrateofmanyCYPenzymes,butthe mainisoenzymeisCYP3A4.Itisadvisedtomonitor amio-darone plasma concentrations and the patient for adverse effects related to amiodarone, including nausea, vomiting, visualchanges,andcardiacarrhythmiasifcoadministration withBOCisrequired.36
Antimicrobialsandantifungals
Ketoconazole,itraconazoleandvoriconazolearestrongCYP3A inhibitors(>5-foldincreaseinexposure,or>80%decreasein clearanceofsubstrate).Fluconazoleisamoderate inhibitor (2- to <5-fold increase in exposure or 50–80% decrease in clearanceofsubstrate).37 Conversely,ketoconazoleand
itra-conazolearemetabolizedonlybyCYP3A4,fluconazoleisnot metabolizedbyCYPandvoriconazoleissubstrateofCYP2C9, 2C19and3A4.
Otheragents
AlthoughtheinteractionbetweencolchicineandBOCorTVR hasnotbeenstudiedyet,aninteractionbetweencolchicine andclarithromycin,astrongCYP3A4inhibitor,resultedinfatal colchicine toxicity.Itisadvisedtotreatthegout flarewith reducedcolchicinedoseto0.6mgtabletforonedose,followed by0.3mgonehourlater,withtherepeateddosenoearlierthan 3days.Forprophylaxisofgoutflare,reductionofcolchicine fromanoriginaldoseof0.6mgtwicedailyto0.3mgoncedaily orfromanoriginaldoseof0.6mgoncedailyto0.3mgonce everyotherdayisrecommended.Forthetreatmentof famil-ialMediterraneanfever,themaximumdailycolchicinedose shouldbenomorethan0.6mgdaily(0.3mgtwicedaily).36
Coadministration ofBOCor TVRand domperidone may result in significantly increased plasma concentrations of domperidone,withriskofseriouscardiacevents(ventricular arrhythmiasand suddencardiac death).Case–control stud-ieshavedemonstratedanassociationofseriousventricular arrhythmiasandsuddencardiacdeath,particularlywith dom-peridonedosesgreaterthan30mg/dayandinpatientsolder than60years.Domperidoneshouldbeinitiatedatthelowest possibledose andtitratedwithcaution.Itmust be discon-tinuedinthepresenceofdizziness,palpitations,syncope,or seizure.Dosageadjustmentsmadeduringconcomitantuseof TVRneedreadjustsafterTVRtherapyiscompleted.36
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