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European Journal of Endocrinology 10.1530/EJE-17-0886 produced by theadrenal cortex ( disorder causedbyprolonged exposuretocorticosteroids Endogenous Cushing’s syndrome(CS)isan endocrine Introduction be reversedontimelydiscontinuationofKTZ. months oftreatment.Liverenzymeabnormalitiesusually occurredwithinfourweekswereasymptomaticandcould Conclusions metastases. Two patientsrecoveredondiscontinuationofKTZandtheremainingpatient diedofunrelatedcauses. the firstmonthoftreatment).Fivepatientshadmildliver functionabnormalitiesatbaselineandtwohadprovenliver and twointheKTZ-switchcohort(3.3%)developedliverinjury, consideredrelatedtoKTZinthreecases(allKTZ-naïve abnormalities observedwereasymptomaticmildincreasesofliverenzymes.FourpatientsintheKTZ-naïvecohort (8.5%) Results (upper limitofnormal),totalbilirubin alkaline phosphatase, of ketoconazole(KTZ-switchcohort).Liverfunctionmarkers(alaninetransaminase(ALT), aspartatetransaminase(AST), Methods Design was todocumentchangesinliverfunctionpatientswithCStreatedKTZ. associated withseverehepatotoxicity, littleinformationisavailableabouthepaticsafetyinCS.Theaimofthisstudy Objective Abstract *(Details oftheCompassionateUseProgrammeparticipantsispresentedinAcknowledgementssection) Hospital, Marseille,France Endocrinology, AixMarseilleUniversite,CNRSUMR7286,AssistancePublique-HopitauxdeMarseille,LaConception métabolisme, AssistancePublique–HôpitauxdeParis,HôpitalPitié-Salpêtrière,France,and Grenoble, France, d’Endocrinologie-Diabétologie-Nutrition, CHUGrenoble-Alpes,Grenoble,France, Maladies Métaboliques,HôpitalHuriez,CentreHospitalierRégionalUniversitairedeLille,INSERMU1190,EGID,France, Unit 1016,InstitutCochin,CentreNationaldelaRechercheScientifique(CNRS)UMR8104,Paris,France, France, Reproduction, AssistancePublique–HôpitauxdeParis,HôpitalBicêtre,LeKremlinBicetre,France, 1 Rita Chadarevian Jacques Young Programme inFrance syndrome: results ofaCompassionateUse Hepatic safetyofketoconazoleinCushing’s Univ Paris-Sud,FacultédeMédecineLeKremlinBicetre,France, https://doi.org/10.1530/EJE-17-0886 www.ej Clinical Study 4 e-online.org Department ofEndocrinology, Metabolism,andDiabetes,InstitutNationaldelaSantéetRechercheMédicale(INSERM) : AnobservationalprospectiveFrenchcohortstudy(CompassionateUseProgramme(CUP)). : Overall,108patientswereanalysed(47KTZ-naïve;61KTZ-switch).ThemedianKTZdosewas600 : EnrolledpatientswerestratifiedintoaKTZ-naivecohortandalreadytreatedbyanotherformulation : Ketoconazole(KTZ)isoneoffewavailabletreatmentsforCushing’s syndrome(CS).AlthoughKTZhasbeen : Thesefindingshighlighttheneedforclosemonitoring ofliverenzymesespeciallyduringthefirstsix 8 INSERM U1036,iRTSV-BCI, CEA-Grenoble,Grenoble,France, 1 , 2 , 3 9 , Jérôme Bertherat , 10 and γ -glutamyltransferase andbilirubin)weremonitoredatregularintervals.PatientswithALT Frédéric Castinetti 5 © 2018EuropeanSociety ofEndocrinology J Young andothers 1 > , 2 4 2 , Marie Christine Vantyghem × ). Thefirst-line
ULN orbothALP Printed inGreatBritain 11 onbehalfoftheCompassionalteuseProgramme* 2 > Service d’EndocrinologieetdesMaladiesdela 2 adrenocortical tumour( ectopic neuroendocrine-secreting ACTH tumour or adenoma, treatment ofCSisremoval ofthepituitary × syndrome Ketoconazole inCushing’s 9 HRA France,Paris,
Published byBioscientifica Ltd. ULN andALT 7 Faculté deMédecineUniversitéGrenoble-Alpes, 5 , Olivier Chabre 11 3 > Department of INSERM U1185,LeKremlin-Bicetre,
ULN wereconsideredtohaveliverinjury. 5 Service d’Endocrinologieet 10 Service d’endocrinologie- Downloaded fromBioscientifica.com at09/27/202101:23:58AM 1 , 3 6 , ). Medicaltreatmentmaybe 7 , 8 , Salima Senoussi (2018) Endocrinology European Journal of to JYoung should beaddressed Correspondence [email protected] Email 6 Service 178
178 :5 , 447–458 mg/day. Most
447 > 9 , 3 –458 × ULN via freeaccess European Journal of Endocrinology www.eje-online.org authorisation forKTZasanantifungaldrugin2013( European Medicines Agency (EMA) withdrew marketing equivalent antifungalefficacyandlowertoxicity, the and theavailabilityofalternativeantifungalagentswith ( other clinicalsymptomsofhepatitisandliverfailure drug hadbeencontinuedaftertheonsetofjaundiceand CUP. IncontrasttorandomisedPhase IIIclinicaltrials, KTZ inthetreatmentofCS be monitoredthroughoutthe the Frenchhealthauthorities requestedthatthesafetyof 2015. Asaconditionofthe implementationoftheCUP, established inFrance,which ranfromJune2014toMarch 2015, aformalcompassionateuseprogramme(CUP)was Europe andthelaunchofKTZHRAinFranceMarch years ofage.Whileawaitingmarketingauthorisation in the treatmentofCSinadultsandadolescentsovertwelve application inEuropefortheuseofKTZspecifically time, a new manufacturer (HRA Pharma) filed a new drug use basiswhilestockslasteduntilJune2014.Atthesame available exclusivelyforthesepatientsonacompassionate alternatives forpatientswithCS,oralKTZremained suspended in2011.However, intheabsenceoftherapeutic of KTZ( the marketingauthorisationfororalformulations without medicaltreatment,especiallyinFrance,where This leftpatientswithCSsuccessfullymanagedKTZ ( adequately asspecifiedintheprescribinginformation in patientswhoseliverfunctionwasnotmonitored when used as antifungal therapy in community medicine fact rare( ( liver enzymesarecommoninpatientstreatedwithKTZ life-threatening complication. of severehepatotoxicity( manifestations ofCS,itsuseischallengingduetotherisk lowering circulating cortisol and in reducing the clinical of CSonanoff-labelbasis.AlthoughKTZiseffectivein This agenthasbeenusedfordecadesinthetreatment corticosteroid synthesis andmetabolism( cytochrome P450enzymesthatplayacentralrolein antifungal agent( (KTZ), adrugoriginallydevelopedandmarketedasan synthesis maybeofuse( after surgery. Inthiscontext,drugsthatinhibitcortisol failure or ofrecurrence of CS possible, in case of surgery ( with radiotherapytocovertheperiodbeforeitiseffective topreparethepatientor provided ifneededbeforesurgery 13 > 3 13 ). Medical treatment is also used when surgery isnot ). Medicaltreatmentisalsousedwhensurgery Clinical Study 1 case/10treatedsubjects),severehepatotoxicityisin , , Although moderate and asymptomaticincreases in 17 16 ). GiventhehepatotoxicriskassociatedwithKTZ, , Nizoral 17 13 ). In particular, in cases which were fatal, the , 14 ; JanssenCilag)asanantifungaldrugwas , 15 5 ). Thishasprincipallybeenreported ), whichcaninhibitseveralofthe 4 ). Onesuchdrugisketoconazole 11 , 12 J Young andothers ), ararebutpotentially 6 , 7 , 8 , 9 , 10 18 ). ). Guidelines forGoodClinicalPracticeandtheprinciples 2015 and the database locked on 9th April 2015. February with KTZ.PatientswereenrolledbetweenJune2014and of theFrenchCUPcohorttreatedinareal-worldsetting study This wasaprospective,longitudinal,observational Subjects andmethods compare liversafetyaccordingtothetreatmentduration. CS receivingKTZinareal-lifetreatmentsettingandto the hepaticsafetyofKTZinacohortpatientswith care. patients followedinareal-worldsettingofeveryday studyofacohort tolerability throughanobservational on theefficacyofdruginquestion,buttodocument CUP isnotintendedtoprovidedefinitiveinformation authorisationofuseinthecontexta the temporary procedures, andwereinvited toprovidewritteninformed information onthegoalsof thestudyandonfollow-up enrolment, all eligible patients were provided with the upperlimitofnormal (ULN) wereexcluded.Before or withserumliverfunction markersabovetwotimes In particular, patients withacuteorchronicliverdisease medication, asspecifiedintheprescribinginformation. to KTZ and were not taking any contraindicated associated verified thatalleligiblepatientshadnocontraindication available wereeligibleforinclusionintheCUP. Itwas was for whombaselineinformationondiseasehistory for thepatient. deliver thedruginordertoensurecontinuityoftreatment even iftheyfailedtodoso,HRAPharmacontinued to regarding the follow-up of all included patients. However, the CUP, physicianswereexpectedtoprovideinformation Pharma foranindividualpatientwithCS.Accordingto could participateintheCUPbyfilingarequesttoHRA All hospitalendocrinologistswishingtoprescribeKTZ Participants consent wasobtainedfromeachpatientpriortoinclusion. database wererenderedanonymous.Written informed for KTZfromHRAPharma.Allpatientdatainthestudy health authoritiesaspartofthemarketingapplication study protocolwassubmittedandapprovedbytheFrench legislation andguidelinesforcompassionateuse.The all subsequentamendmentsandrelevantnational laid downintheDeclarationofHelsinki(1964)including syndrome Ketoconazole inCushing’s The studywasconductedinconformitywiththe The objectiveofthepresentstudyistodocument Patients withadiagnosisofCSfromanycauseand Downloaded fromBioscientifica.com at09/27/202101:23:58AM 178 :5 448 via freeaccess European Journal of Endocrinology treatment withKTZfromHRA Pharmawasstarted. contraindications specified in theprescribinginformation, markers. Intheabsenceofliver functionabnormalitiesor A bloodsamplewastaken forassayofliverfunction in particularandobtainedwritten consenttoparticipate. treatment ingeneralandaboutsignsofhepatotoxicity physician informedthepatientaboutrisksof serum liverfunctionmarkers.Attheinclusionvisit, visit andseveralfollow-upvisitsformonitoring of the conductofstudy. Thestudyinvolvedan inclusion procedures. However, someguidancewasprovidedon study conditions, therewerenoformalormandatory study under usual care As this was an observational Study procedures described earlier. and subsequentdosechangecouldbeperformedas KTZ-switch cohortcontinuedattheirpreviousKTZdose treatments anddiscontinuationofKTZ.Patientsinthe including changes to KTZ dose, changes in adjunctive occurring overthestudyperiodhadtobedocumented, day intwoorthreedivideddoses.Allchangestreatment necessary, thedosecouldbeup-titratedto800–1200 fewdays)andofthetolerabilitytreatment.If every freecortisollevelsassayed (determined from24-hurinary discretion asafunctionofthechangeincortisollevels doses, whichcouldthenbeadjustedatthephysician’s initial dosewas400–600 For patients in the KTZ-naïve cohort, the proposed administered accordingtotheprescribinginformation. All patients received KTZ 200 Treatments between oneandsixmonths. over sixmonthsandtheotherpreviouslytreatedfrom subdivided intotwosubgroups,onepreviouslytreatedfor for thepurposesofcertainanalyses,switchcohortwas and therecommendedmonitoringschedule.Inaddition, the impactofoveralltreatmentdurationonliversafety The purposeofthisstratificationwastotakeinto account treatment uptofourweekspriortheinclusionvisit. cohort, patientscouldbeincludediftheyhadstarted before inclusion (KTZ-naïve cohort). In the KTZ-naïve who hadnotreceivedtreatmentwithKTZ ≥ the previouslymarketedproduct(KTZ-switchcohort)for into twocohorts,onewhohadalreadybeentreatedby consent. Enrolledpatientswereprospectivelystratified 1 month ofinclusionandasecondcohortpatients 1 month Clinical Study mg/day intwoorthreedivided mg tablets (HRA Pharma) J Young andothers < month 1 mg/ (GGT), alkalinephosphatase(ALP)andtotalbilirubin aspartate aminotransferase(AST), markers evaluatedwerealanineaminotransferase(ALT), each follow-upvisitatthephysicians’discretion.The study. Theseweretobemeasuredatinclusionand outcomes of this observational one of the primary The evolutionofserummarkersliverfunctionwas Outcome variables threemonths. planned every treated foroversixmonths.Aftermonths,visitswere three monthsaftertheswitchifpatienthadbeen been treatedwithKTZbetweenoneandsixmonths, planned onemonthaftertheswitchifpatienthad For patientsintheKTZ-switchcohort,firstvisitwas first monthandonceathereafter forsixmonths. weekforthe naïve cohortweretobemonitoredevery total bilirubin ALT if oneofthefourfollowingconditionswasmet:(i) pattern ofliverinjury. was usedinstead.Thisratio(R)todefinethe calculated. IntheabsenceofameasurementALT, AST ALT toALP(bothexpressedasmultiplesoftheULN)was theratioofrange (ULN).Ifelevationswereobserved, expressed asmultiplesoftheupperlimitnormal the normalrange.Levelsofeachserummarkerwere laboratories, whichappliedtheirowndefinitionsof (TB). Assayswereperformedinlocalaccredited and treatmentcontinuedthereafter atthelowerdose. monitored tightlyuntilthe liver functiontestnormalised had to be decreased by If thelevels were KTZ hadtobediscontinued immediatelyandirrevocably. possible causalrelationshiptoKTZtreatment. were reviewedbyanexperthepatologistwhoassessed a just havingliverfunctiontestabnormalities.Allcases which remainedbelowthesethresholdsweredefined as mixed. Patientswhohadabnormallivertestsvaluesbut and R was normal or, if ALT and ALP were both increased and was consideredtobecholestaticifALP ALT and ALP were both increased and hepatocellular ifALT ALT syndrome Ketoconazole inCushing’s was With respecttofollow-upvisits,patientsintheKTZ- The patient was considered to have liver injury The patient was considered to have liver injury If thelevelofanyliverfunctionmarkerwas > > R 3 ULN. The pattern of injury was considered to be ULN. The pattern of injury was ≤ × 2. IfbothALPandtransaminaseswereelevated
ULN, (ii) AST > 2 but > 2 × >
≤ ULN or(iv)bothALP ULN but 5, thepatternwasconsideredtobe > 3 ≥ > Downloaded fromBioscientifica.com at09/27/202101:23:58AM × 200 3
ULN andALPwasnormalor, if ×
ULN if ALT mg per day and the marker < 3 ×
ULN, the dose of KTZ γ -glutamyltransferase R 178 was > www.eje-online.org :5 2 × ≤ > >
3 5. The pattern ULN andALT 2 × × L, (iii) ULN, ≥ L and ULN 3 × 449 ULN, via freeaccess European Journal of Endocrinology www.eje-online.org treated patients, 51 had been treated for over six months. treated patients,51hadbeen treatedforoversixmonths. previously beentreatedwith KTZ.Ofthese61previously all-treated setswereKTZ-naïve andtheremaining61had constitute theall-treatedset. Forty-sevenpatientsinthe These patients(75%women, meanage51.3(range:11–86)) function markerswasprovidedbythetreatingphysician. were treatedandatleastonepost-treatmentmeasureofliver hypercalciuria; 9patients).Ofthesepatients,108(56.5%) than CS(suchasprostaticcarcinoma orhypercalcaemia- (12 patients)orrequestsforuseinindicationsother due toabnormalitiesinliverfunctiontestsatscreening ( the patientfulfilledeligibilitycriteriaandwasenrolled endocrinologists in100hospitals.In191cases(90.1%), A totalof212treatmentrequestswerereceivedfrom133 Participants Results were performedusingSAS,version9.4. and percentages. Statistical programmingandanalyses Categorical variablesarepresentedasfrequencycounts orasmedianvalueswithrange. 95% confidenceintervals) presented asmeanvalues was essentiallydescriptive.Continuousvariablesare cohort andforbothcohortscombined.Theanalysis separately fortheKTZ-naïvecohortandKTZ-switch function markers was available. Analyses were performed and forwhomatleastonepost-treatmentmeasureofliver as allpatientsparticipatingintheCUP, treatedwithKTZ The analysiswasperformedontheall-treatedset,defined Statistical analysis patients inordertofacilitateretrievalofCRFs. was madewithafurthereightsitesincludingthreeorfour patients tohelpCRFcollection,andtelephonecontact were organisedforsixsiteswhoincludedmorethanthree Although there was no formal monitoring, on-site visits and, inpractice,theCRFwasnotfilledsystematically. the studyinapaperCRF, butthiswasnotmonitored Physicians were expected to record all data relating to Data quality and classifiedusingstandardisedMedRAterminology. form (CRF).Theinvestigators’ reaction occurringunderKTZtreatmentonthecasereport i. 1 Fig. Clinical Study Investigators were asked to record any adverse drug ). The remaining 21 patients were not enrolled, ). The remaining 21 patients were not enrolled, ±
standard deviations(orwith verbatim J Young andothers wasconsolidated related toKTZ.Theadverseeventsleadingtreatment twelve patients, the reasons for discontinuation were not whom KTZ treatment was ineffective. For the remaining andfourpatientsfor who werescheduledforsurgery considered tobepossiblyrelatedKTZ,sevenpatients KTZ treatment,sevendiscontinuationsforadverseevents deaths, none of which were considered to be related to discontinued theCUP. Theseincludedninepost-treatment received morethanonesuchdrug). with mitotaneandfivecabergoline(somepatients namely twentypatientstreatedwithmetyrapone,seven patients werereceivinganothercortisone-loweringdrug, are presentedin months).Themainreasonsforusingketoconazole 2.5 monthsvs been diagnosedforlonger(median:69.7 months).Patientsintheswitchgrouphad range: 2–286 the CUPwas50.7 The meandurationofKTZtreatmentbeforeinclusionin naïve andtheKTZ-switchcohorts(range200–1200 the medianfinaldosewascloseto600 patients requiredupwardtitrationoftheinitialdose,and for theall-treatedsetarepresentedin The meandoseofKTZandthetreatment duration Ketoconazole treatment one caseeachofalopeciaandgeneralisedpruritus. (discussed below),twocasesofadrenalinsufficiencyand discontinuation included three casesofliverinjury Patient distribution.FU,follow-up; KTZ,ketoconazole. Figure 1 syndrome Ketoconazole inCushing’s In total,39patientsintheall-treatedset(36.1%) al 1 Table ±
62.0 months (median: 26 months; months; months(median:26 62.0 Downloaded fromBioscientifica.com at09/27/202101:23:58AM . At the time of inclusion, 28 . At the timeofinclusion,28 178 mg inboththeKTZ- :5 al 2 Table . Most mg). 450 via freeaccess European Journal of Endocrinology the ULNgenerallycorresponded toamodestrisefrom andtheelevationsabovechanges werenotobserved, exposed toalongertreatment duration,suchabrupt the KTZ-switchcohortwho, bydefinition,havebeen within the first month of treatment. In contrast, in corresponded tosharprisesinALT levelsoccurring KTZ-naïve cohort,themajorityofelevations in ALT, ASTandALP inindividualpatients.Inthe the eligibilitycriteriaforstudy. although these did not exceed 2 of patients presented elevations of AST or ALT at baseline, forAST,also observed ALPandGGT. Overall,around10% baseline. In this patient, on-treatment elevations were and whoalsopresentedelevationsofALT andGGTat syndrome andlivermetastases(Patient3; a patientintheKTZ-naïvegroupwithanectopicACTH 7 one patient.ThehighestelevationofALT was observed GGT, in whereas elevations in TB were only observed for cohort. Elevationsweremostcommonlyobserved greater intheKTZ-naïvecohortthanKTZ-switch of allthemarkersstudiedtendedtobemorefrequentand treatment monthsandKTZ-switchwithapreviousdurationof 6 with apreviousdurationoftreatmentbetween1and available visitforthreegroups(KTZ-naïve,KTZ-switch The evolutionofliverenzymesfrombaselinetothelast Liver functiontests ACC, adrenalcellcarcinoma;ACTH,adrenocorticotropichormone;CS,Cushing’s syndrome. treatment wasnotdocumentedforthefourremainingcases.The‘other’categorymayinclude,example,patientrefusalsurgery. Percentages arecalculatedwithrespecttothenumberofdocumentedcases(46inKTZ-naïvecohortand58KTZ-switchcohort);reasonfor Other CS ACTH-independent disease Cushing’s ACC Total KTZ-switch cohort( Other CS ACTH-independent disease Cushing’s ACC Total KTZ-naïve cohort( was notdocumentedforthefourremainingcases.The‘other’categorymayinclude,example,patientrefusalsurgery. respect tothenumberofdocumentedcases(46inKTZ-naïvecohortand58KTZ-switchcohort);reasonfortreatment Table 1 × Clinical Study Ectopic ACTHsecretion Ectopic ACTHsecretion
ULN measuredoneweekafterinclusionandconcerned iue 2 Figure Causes of CS and medical indication of ketoconazole prescription in the all-treated set. Percentages are calculated with Causes ofCSandmedicalindicationketoconazoleprescriptionintheall-treatedset.Percentagesarecalculatedwith ≥ 6 months) is presented in 6 months) presentsthetime-courseofchanges n n =47) =61) Awaiting surgery 13 (28.3%) 4 (6.9%) 4 (6.9%) 1 (2.2%) 2 (4.3%) 8 (17.4%) 2 (4.3%) J Young andothers None None None None None ×
ULN, consistent with
Table 3 . Elevations al 4 Table Surgery ineffective > 24 (41.4%) 24 (41.4%) 7 (15.2%) 7 (15.2%) ULN None None None None None None None None ),
Mean Final doseofKTZ(mg/day) (all-treated set,seealsoFig. 1). Table 2 for whomdatawereavailable. The available). date ofdataentryinthedatabaseif thelastdosedatewasnot the KTZstartdateinCUPand lastKTZdosingdate(orthe a (range) Treatment durationinCUP(months) Median ( criteria forliverinjury in theKTZ-switch cohort (3.3%), fulfilled theprespecified Six patients,fourintheKTZ-naïvecohort(8.5%)andtwo Liver injury ( although elevationsweregenerallyoflowermagnitude forchangesinASTandALP,patterns wereobserved Veryto underneaththethresholdwereobserved. similar cohort, modestfallsinALT levelsofasimilarmagnitude throughout thestudyperiod.Inotherpatientsinthis level alreadyclosetothethresholdandatasimilarrate syndrome Ketoconazole inCushing’s The durationofexposuretoKTZiscalculated asthedifference between Fig. 2 ≥ n ≥ < n 6 months 1 to 1 month n valuesatthetopofeachboxcorrespond tothenumberofpatients ). ± <
6 months Not eligiblefor Treatment withketoconazoleduringtheCUP s . d 14 (24.1%) 22 (37.9%) 12 (26.1%) . 5 (8.6%) 3 (5.2%) 1 (2.2%) 7 (15.2%) 4 (8.7%) surgery None None None None KTZ naïve 600 (200–1200) 27 (58.7%) 15 (32.6%) Downloaded fromBioscientifica.com at09/27/202101:23:58AM Table 4 4 (8.7%) 679 43 46 ± 277 10 (21.7%) 14 (30.4%) ( n ). Inallfourcasesinthe 1 (1.7%) 2 (3.4%) 5 (8.6%) 8 (13.8%) 1 (2.2%) 1 (2.2%) 2 (4.3%) =47) a None None None Other
178 www.eje-online.org :5 KTZ switch 600 (200–1200) 40 (65.6%) 18 (29.5%) 3 (4.9%) 629 59 61 47 (81.0%) 58 (100%) 12 (41.7%) 23 (50.0%) 46 (100%) ± 6 (10.3%) 5 (8.6%) 2 (4.3%) 1 (2.2%) 8 (17.4%) 265 None None Total ( n 451
=61) via freeaccess European Journal of Endocrinology www.eje-online.org 3 2 N AST ALT 3 2 ULN ALP, alkalinephosphatase;ALT, alanineaminotransferase;AST, aspartateaminotransferase;GGT, gamma-glutamyl-transferase. the numbersofpatientsreachingindicatedlevelatanystageoverstudy. The denominator‘ 3 Total bilirubin GGT 3 2 ULN GGT 3 2 ULN ALP as arapidup-titration,whereas thiswasthecaseforless exposed toadoseof and oneofthetwopatients in theswitchgrouphadbeen inthenaïvegroup patients whodevelopedliver injury in liverfunctiontestsatbaseline. With respecttodose,all and abnormalities presented acholestaticpatternofinjury two cases.ThecasesintheKTZ-switch cohort both at baseline,togetherwithdocumentedmetastases in injury. All had mild abnormalities in liver function tests were asymptomaticandshowedmixedpatternsofliver normalised. TheothercasesintheKTZ-naïvecohort of KTZ,thesesymptomsdisappearedandtransaminases KTZ. Jaundicedidnotdevelop.Upondiscontinuation (nausea andvomiting),withinonemonthofstarting (ALT (Patient 2)presentedahepatocellularpatternofinjury month oftreatment.OnepatientintheKTZ-naïvecohort occurredduringthefirst KTZ-naïve cohort,liverinjury ALT reaching theindicatedlevelatanystageoverstudy. with abaselineandatleastonefollow-updeterminationofthemarkerinquestion.Datapresentnumberspatients Table 3 > Abnormal valueatbaseline > > Abnormal valueatbaseline > Abnormal valueatbaseline > Abnormal valueatbaseline Abnormal valueatbaseline Clinical Study × × × × × × × × × ULN atleastoncepost-baseline ULN atleastoncepost-baseline ULN atleastoncepost-baseline ULN atleastoncepost-baseline ULN atleastoncepost-baseline < ULN ULN ULN ULN ULN ULN ULN ULN ULN AST ≥ ≥ < < < ≥ 3 5 GGT ALP ALT 5 × × ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ < Evolution ofliverfunctionmarkersoverthecoursestudy. Thedenominator‘ ×
ULN ULN) associated with non-specific clinical signs GGT GGT GGT ALP ALP AST AST ALT ALT 2 ULN < < < × 2 2 2 ULN < < × < < < < × n < < < × 5 3 ULN ’ indicatesthenumberofpatientswithabaselineandatleastonefollow-updeterminationmarkerinquestion.Datapresent 5 3 ULN 5 3 5 5 3 ULN × × × × × × × × × ULN ULN ULN ULN ULN ULN ULN ULN ULN ≥ 800 mg, eitherastheinitialdose or J Young andothers KTZ-naïve 10 (34.5%) 12 (38.7%) 10 (32.3%) 18 (60.0%) 1 (0.5%) n n n n n None =29 =31 =31 =20 =30 12 1 3 6 5 1 2 9 4 4 0 3 3 1 5 3 3 7 6 ( n =47) to liver enzymes,thedoseofKTZ wassubsequentlyreduced injury, thedosewascontinued.Followingafurtherrise in two casesintheKTZ-switch groupwithcholestaticliver patient’s overallwell-beingthanuncontrolled CS.Inthe dysfunction wasconsideredtobelessdetrimentalthe was terminallyill,thedoseincreasedsincehepatic the remainingpatientinKTZ-naïvegroup,who due to a likely causal relationship withtreatment.In 3), allintheKTZ-naïvegroup)KTZwasdiscontinued developed jaundice.Inthreecases(Patients1,2and bilirubin levelclosetotheULNatinclusionsubsequently on provided inthe transaminases with respect to maximal KTZ dose is andelevationsof on thedistributionofliverinjury than athirdofpatientwithoutliverinjury. Information syndrome Ketoconazole inCushing’s ≤ Supplementary data Supplementary KTZ-switch One of these two cases of liver injury (Patient 5),witha One ofthesetwocasesliverinjury 600 mg/day. 1 (25.0%) 1 (20.0%) (1–6 months) None None None None None None n n n n n =4 =4 =4 =1 =5 0 0 1 1 0 0 0 0 0 0 0 0 1 0 0 0 1 Supplementary data Supplementary givenattheendofthisarticle). n
( Downloaded fromBioscientifica.com at09/27/202101:23:58AM n ’ indicatesthenumberofpatients =10) KTZ-switch 178 online(seesection 10 (31.2%) :5 4 (13.3%) 4 (11.1%) 8 (22.9%) ( n n n n n None None > =30 =36 =35 =24 =32 6 months) 0 0 4 1 0 0 4 2 0 0 1 7 5 0 1 2 1 6 6
( 452 n =51) via freeaccess European Journal of Endocrinology
Table 4 Characteristics of patients fulfilling the prespecified criteria for liver injury. Clinical Study
Abnormal liver function Total Visit at Liver Liver tests at Initial dose treatment Dose at LIO which LI function Clinical CS aetiology metastases baseline (mg/day) duration (mg/day) detected tests at LIO presentation LI type Outcome Naïve Patient 1 Ectopic ACTH Yes AST 1.9 1000 3 days 1000 Week 1 AST 4.5 Asymptomatic Mixed KTZ stopped syndrome ALT 1.5 ALT 1.0 for AI day 3 ALP 1.2 GGT 4.1 Outcome ALP 1.1 unknown Patient 2 Cushing’s Unknown None 1000 20 days 1000 Week 3 AST 2.4 Nausea and Hepatocellular KTZ stopped
disease ALT 5.1 vomiting day 20 J Young andothers GGT 1.1 Recovered ALP < 1 by day 40 Patient 3 Ectopic ACTH Yes ALT 2.1 600 7 days 1200 Week 1 AST 2.6 Asymptomatic Mixed KTZ stopped syndrome GGT 13.4 ALT 7.4 day 7 ALP 1.5 GGT 16.4 Recovered ALP 2.5 by day 43 Patient 4 ACC Unknown ALT 1.7 400 31 800 Week 3 AST 1.6 Asymptomatic Mixed KTZ dose GGT 1.9 ALT 6.6 increased GGT 4.2 day 28 ALP 1.4 (terminal severe CS) Death due to PE day 31 syndrome Ketoconazole inCushing’s Switch* Patient 5 Ectopic ACTH Probable ALT 1.8 1200 15 days 1200 Week 1 AST 1.5 Jaundice Cholestatic KTZ dose syndrome on GGT 13.3 ALT 3.5 reduced chemotherapy GGT 37.6 (600 mg) ALP 3.3 day 12 Death due to pulmonary distress day 15 Downloaded fromBioscientifica.com at09/27/202101:23:58AM Patient 6 ACC Unknown AST 1.6 600 96 days 600 Week 1 AST 2.7 Asymptomatic Cholestatic KTZ dose GGT 1.3 ALT < 1 reduced ALP 1.9 GGT 1.1 (400 mg) ALP 2.5 day 62 Death due to
PE day 96 178 www.eje-online.org :5 *Both patients in the KTZ-switch group had been treated for less than six months before enrolment into the cohort. Liver function data are presented as multiples of the upper limit of normal (ULN). Baseline liver function data are only presented if >ULN. ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; AI, adrenal insufficiency; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CS, Cushing’s syndrome; GGT, γ-glutamyltransferase; KTZ, ketoconazole; LI, liver injury; LIO, liver injury onset; ND, not determined; PE, pulmonary embolism. 453 via freeaccess European Journal of Endocrinology www.eje-online.org also treatedwithanothersteroidogenesisinhibitor. remaining four. Importantly, threeofthesepatientswere for twopatientsandmaintainedunmodifiedthe which werereducedforonlyonepatient,discontinued had receivedrelativelyhighdosesofKTZ(600–1000 hypercortisolaemia rapidly. Inthiscontext, all patients adrenal functioninordertorecovercontrolofsevere to theintentionofphysicianblockandreplace adrenal insufficiency may in some cases correspond naïve cohort)andonecaseofheadache. The casesof eight casesofadrenalinsufficiency(allintheKTZ- (describedearlier), including sixcasesofliverinjury any individualpatientmayexperiencemorethanoneADR. pruritus, astheniaanddyspepsia(1patienteach).Notethat alopecia, patients), headache(2patients)anderythema, adrenal insufficiency(7patients),jointpain/stiffness(4 remaining 29ADRs were ‘drug ineffective’ in 13patients, identified wererelatedtoabnormalliverfunctiontests.The drug reaction(ADR).Themajority( Overall, 34patients(31.5%)experiencedatleastoneadverse Other safetyvariables Clinical Study Thirteen patients experienced fifteen seriousADRs, J Young andothers 50 ) of the 79 ADRs ) ofthe79ADRs mg), 600 KTZ atdailydosesrangingfrom200to1200 their evolutionovertimeinpatientswithCStreated we havedescribedchangesinliverfunctionmarkersand sample of patients in France. In this prospective study, a frameworktocollectsuchdatainrelativelylarge KTZ as an acute antifungal treatment. The CUP provided higher dosesandforlongerdurationthanpatientsusing KTZ inpatientswithCSwhoarepotentiallyexposedto Little informationisavailableaboutthehepaticsafetyof Discussion distress(onecaseeach). syndrome andrespiratory cases) andsepticshock,occlusivesyndrome,tumoural embolism (two progression (three cases), pulmonary KTZ treatment.Thesedeathswereattributedtocancer KTZ treatment,noneofwhichwasconsideredrelatedto use occurred. Observed increasesintransaminasesorALP use occurred.Observed following treatment with KTZ. No deaths related to KTZ no unanticipated hepatic safety issue was observed syndrome Ketoconazole inCushing’s mg) for periods of up to one year. In this population, Overall, ninedeathswerereportedafterstarting phosphatase. aminotransferase; E,F:alkaline aminotransferase; C,D:aspartate switch cohort.A,B:alanine in levels forthesixindividualpatientslisted indicate theevolutionofliverenzyme limit ofnormal(ULN).Theredlines horizontal bluelinerepresentstheupper W0: InitiationofKTZ-CUPtreatment.The enzymes group presentedanelevationofliver for lessthansixmonthsintheKTZ-switch represented (noneofthepatientstreated before inclusionintheCUPare only patientstreatedforoversixmonths are presented.IntheKTZ-switchcohort, and thenormalrangeweredocumented value, atleastonepost-treatmentvalue Only patientsforwhomthebaseline Each linerepresentsanindividualpatient. available visitinindividualCSpatients. phosphatase frombaselinetothelast Evolution oftransaminasesandalkaline Figure 2 Table 4 Downloaded fromBioscientifica.com at09/27/202101:23:58AM > . A,C,E:naïvecohort;B,D,F: 3 ×
ULN). M,month;W, week; 178 :5 mg (median 454 via freeaccess European Journal of Endocrinology characteristics. ofproduct provided bythemanufacturer inthesummary respecting carefullytheprescribing recommendations liver functiontestsbefore startingtreatmentand emphasisetheimportanceofperforming observations in thesepatientscannotbeexcluded.Nevertheless, subclinical liverdisease,suchassteatosisorviralhepatitis, already present at inclusion. Pre-existing undiagnosed or mildabnormalitiesinliverfunctiontests(fivepatients) the presenceofidentifiedlivermetastases(twopatients) cases dueto KTZ wasquestionableincertainliverinjury 2 elevations ofliverenzymes,intwocasesexceeding 400–600 KTZ washigherthantherecommendedstartingdose of enzymes normalised.Itisofnotethattheinitialdose In thepatientsinwhomKTZwasdiscontinued,liver observed. which mayhavecontributedtotheinjury or pre-existingelevationsintransaminases (or both), KTZ-naïve patients,therewasevidenceoflivermetastases upon discontinuation of KTZ. In the remaining three hepatotoxicity (nauseaandvomiting),whichresolved symptomatic, presentingnon-specificsignsindicativeof one case,withahepatocellularpatternofinjury, was months).Only week–7½ weeks oftherapy(range:1 appearedwithinthefirstsix associated hepaticinjury a previousstudy( of KTZinitiation.Thisisconsistentwithfindingsfrom occurredwithinaroundonemonth cohort, liverinjury tests atbaseline( ( hepatocellular patterntypicalofKTZ-associatedinjury pattern ofinjury, whichwouldbeinconsistentwiththe whom developedjaundice,presentedwithacholestatic cohort. ThetwopatientsintheKTZ-switchcohort,oneof four intheKTZ-naïvecohortandtwoKTZ-switch insufficiency andtwoothercasesduetoADRs. (seebelow),twocasesofadrenal cases ofliverinjury treatment related,includingfourcasesofinefficacy, three discontinuations and10.2%oftreatedpatients)were of theadenoma.Elevendiscontinuations(28.2%all forablation of discontinuationsorpreparationforsurgery of thepatient,whichaccountedforaroundone-quarter unrelated totreatmentwithKTZ,forexample,thedeath the reasonfordiscontinuationwasmostfrequently treatment discontinuationwasrelativelyhigh(36.1%), majority ofcasesasymptomatic.Althoughtherate the firstmonthoftreatmentinitiationandwerein were generallymildormoderate,usuallyoccurredwithin 16 × Clinical Study
ULN, werepresentinfive.Acausalrelationshipwith ). Bothpatientshadabnormalitiesinliverfunction Six cases of liver injury were documentedinourstudy,Six cases of liver injury mg inthreeofthesepatientsandpre-existing 16 13 ), inwhich60%of55casesKTZ- ). InthepatientsinKTZ-naïve J Young andothers each step,onacase-by-casebasis. up-titration withacarefulassessmentofthehepaticriskat of respectingtherecommendedstartingdoseandgradual Ourfindingsreinforce to monthlyintervals. theimportance any doseincreasesshouldbemadein200 control ofcortisolaemia,althoughitisrecommendedthat 1200 400–600 ketoconazole specifiesthattherecommendedstartingdoseis ill patients. However, the prescribing information for been requiredinordertocontrolcortisolaemiaseverely as theinitialdoseorarapidup-titration.Thismayhave had all been exposed to a dose of injury noteworthy thatfiveofthesixpatientswhodevelopedliver the hepatic impact of ketoconazole ( reports, nocleardoserelationshiphasbeenestablishedfor conclusions onpossibledoserelationships.Inprevious or elevatedtransaminases,itisdifficulttodrawfirm analysis of data from 204 studies of use of KTZ principally to differencesincasedefinitions andstudydesign.Ameta- incidence inpatientsusingthis drugasanantifungal,due inpatientswithCSstarting KTZ with of liverinjury treatment ( earlyandarerareaftersixmonths ofcontinuous observed in whichliverenzyme elevations have alsogenerally been function inpatientsusingketoconazoleasanantifungal, CS arebroadlyconsistentwiththeliteratureonhepatic Thesefindings inpatientswith KTZ dosewasobserved. No associationbetweenrisesintransaminaselevelsand normalised afterdiscontinuationofKTZordosereduction. identified duringthefirstmonthoftreatmentand all and prospective data collection. All these elevations were which mayreflecttherelativesensitivitiesofretrospective transaminases wassomewhatlowerthanthatinourstudy, ≥ < and 2012( patients withCStreatedKTZinFrancebetween1995 be comparedwiththoseofaretrospectivecohort200 had beentreatedforoversixmonths.Ourfindingscan rareinthepatientsKTZ-switchcohortwho very first monthoftreatmentintheKTZ-naïvecohortandwere elevations oftransaminases inthesixpatientsdiscussedabove.Allcasesof injury majority ofcasesandonlyfulfilled thecriteria forliver starting KTZ, although these elevations were mildin the function markersappearedinaroundone-thirdofpatients syndrome Ketoconazole inCushing’s 5 5 × × Given the low number of subjects with liver injury Given the low number of subjects with liver injury It is difficult to compare the observed incidence It isdifficulttocompare theobserved In ourstudy, asymptomaticelevatedlevelsofliver
ULN in2.5%.Theproportionofpatientswithelevated in13.5%ofpatientsandincreases ULN wereobserved mg/day on an individual basis to ensure satisfactory mg/day onanindividualbasistoensuresatisfactory mg/day andthatthisdosecanbeincreasedto800– 19 13 , , 15 20 , ), inwhichelevationsoftransaminases 16 , 17 Downloaded fromBioscientifica.com at09/27/202101:23:58AM ). ≥ 2 ×
ULN occurredwithinthe 11 178 ). Nonetheless, it is ). Nonetheless, it is www.eje-online.org mg steps at weekly mg stepsatweekly :5 ≥ mg, either either 800 mg, 455 via freeaccess European Journal of Endocrinology www.eje-online.org been reportedtotriggerelevations oftransaminasesin of liver enzymes should be re-established, since this has enzymes. In case of dose escalation, close monitoring jaundice, should prompt immediate monitoring of liver as unusualfatigue,abdominal pain,nausea,vomitingor any signsorsymptomssuggestiveofliverinjury, such need particularly close follow-up. The appearance of enzyme levelsbetweenULNand2 these patientsisprovided in the recommendedmonitoringofliverfunction in in theprescribinginformation.Analgorithmillustrating on a monthly basis for up to six months, as recommended should be performed at least over the first month and then inpatientstreatedwithKTZ.Weeklyobserved monitoring liver enzymes,whicharebyfarthemostfrequentpicture orofmildasymptomaticincreasesin of hepaticinjury forevidence biochemical monitoringatregularintervals criterionforthisstudy.entry was 6.4 weeks. Abaselinetransaminase level was 200 with clinicalsymptoms( and afurther2.9%(95%CI:0.1–5.7%)showedelevations patients presentedasymptomaticelevationsofALT antifungal reportedthat17.5%(95%CI:11.1–23.9%)of liver functionin137patientstreatedwithKTZasan prospective clinicaltrialthathasspecificallyevaluated the includedstudieswidelyintermsofdesign.Theonly 4.2%, withnoobviousdose–responserelationship,but as anantifungal( Clinical Study Our findingsemphasisetheneedforclinicaland mg and the mean time to onset of elevated ALT 11 ) reportedanincidencerateof3.6– 21 ). Inthisstudy, thedailydose i. 3 Fig. J Young andothers . Patientswithliver ×
ULN atbaseline < ULN wasan > ULT describe the safety of KTZ in everyday care in France.describe the safety of KTZ in everyday a rarediseasetheopportunity tobetreatedand longstanding CS. ketoconazole, notablyinpatients withmoresevereand disease could be useful prior to initiating treatment with manifestations. Assessment of potential subclinical liver transient elastography( with non-invasivetechniquessuchassonography or with longstandingCSandconsiderepisodicassessment be awareoftheriskstructuralliverdiseaseinpatients frame thanthatofthepresentstudy. Physicians should changes intransaminasesandmayrequirealongertime- structural liverdiseasemaynotbeassociatedwithdramatic be addressedinstudiessuchasourssinceprogression of KTZ aggravatesthisriskisunknown.Thiscannoteasily cirrhosis ( steatohepatitis, whichmayevolveintofibrosisor is notuncommonlyassociatedwithnon-alcoholic independentlyoftheuseKTZ( liver injury KTZ iscontinueddespitemarkedliverenzymeelevation. 16 be reducedbyatleast200 with increasesthatdidnotreach3 3 whose transaminases,ALPorbilirubinincreaseabove that KTZshouldbediscontinuedimmediatelyinpatients with respecttohepaticfunction( patients whohavepreviouslytoleratedKTZtherapywell syndrome Ketoconazole inCushing’s × ,
ULN inordertoavoidsevereliverinjury. Inpatients 17 The CUPwasestablished togivepatientswith It shouldbenotedthatCSalsocarriesariskof ), fatal cases have been reported particularly when 23 , 24 ). Whetherlong-termtreatmentwith tests. even afternormalisationofliverfunction 2 patient profileandclinicalstatus. upper limitofnormal. alkaline phosphataseandbilirubin;ULN, aminotransferase, aminotransferase, aspartate LFT, Liverfunctiontests:alanine starting treatmentwithketoconazole. in patientswithCushing’s syndrome Algorithm formonitoringofliverfunction Figure 3 Ketoconazole shouldnotbereintroduced 25 Downloaded fromBioscientifica.com at09/27/202101:23:58AM ), orincaseofsuggestiveclinical mg. Intheliterature( 13 × γ
ULN, thedoseshould -aminotransferase, , 178 17 1 Depending onthe :5 , 19 ). We believe 13 22 , 14 ) and 456 , 15 via freeaccess , European Journal of Endocrinology F Chaveparticipatedasremunerated speakersatconferencesymposia participation inSteeringCommittee meetingsforthisstudy. OCand received reimbursementfromHRA Pharma fortravelinconnectionwith company atthetimeofstudy. J B, FC,OMCVandJYhave S isanemployeeofHRAPharma andRCwasanemployeeofthis Declaration ofinterest EJE-17-0886. This is linked to the online version of the paper at Supplementary data be usedsafelyinpatientswithCS. care istakentomonitorliverfunctioneffectively, KTZcan at thebeginningoftreatmentanduptosixmonths. If the need for close monitoring of liver enzymes especially years. Thesenewdatacollectedprospectivelyhighlight for thetreatmentofCSinpatientsoverage12 of CSforseveraldecades,itisnowauthorisedintheEU drugs, whichmayalsobepresentinthesepatients. or concomitanttreatmentwithotherhepatotoxic for abnormal liver function tests, such as alcohol intake was notpossibletotakeintoaccountotherriskfactors imprecision intheconsolidationofdata.Finally, it 100 participatingcentres,whichmayhaveledtosome conducted accordingtothestandardpracticeof the liverfunctiontestswerenotcentralisedand to providefollow-updata.Anotherlimitationwasthat label basisforoverthirtyyearswithoutanyobligation had been prescribing KTZ to patients with CS on an off- analysis. It should beborne in mindthat physicians As a result, less data than expected were available for the coordinatingcentre,thiscouldnotbeenforced. physicians wereaskedtoprovidefollow-updata and formalmonitoringand,althoughparticipating CUP wasnotaformalclinicaltrialwithestablishedvisits of missingdataespeciallyintheKTZ-switchcohort.The The principallimitationwastherelativelyhighamount findings were evaluated by an experienced hepatologist. individual patientbasis.Theclinicalandbiochemical changes inliverfunctiontestswereanalysedonan of doses.Thedatawerecollectedprospectivelyand to treatmentwithKTZandtreatedawiderange a confirmeddiagnosisofCSwithoutcontraindication unselectedsampleofpatientswithKTZ inanotherwise naturalistic treatment setting reflecting ‘real-life’ use of of thecondition( relatively largenumberofpatientsconsideringtherarity context. Amongthestrengths,studyenrolleda The strengths and limitations of the study reflect this Clinical Study Although KTZhasbeenusedoff-labelforthetreatment 26 ). Thestudywasperformedina J Young andothers https://doi.org/10.1530/
to allthephysicianswhoenteredpatientsintothisCompassionate staff whohaveparticipated inthiscohortstudy. Theauthorsaregrateful The authorswishtoexpresstheirgratitudeallthepatientsandclinic Acknowledgements the finalversion. contributed tothepreparationofmanuscript,reviewedandapproved final dataanalysisandthepreparationofthismanuscript.Allauthors the designofprotocolandconductstudy. Soversawthe R C,anemployeeofthestudysponsorattimestudy, oversaw advisory panelforthisstudyandrecruitedpatientsintotheprogramme. The academicauthors(JY, JB,OC,MCV, FC)constitutedthescientific Author contributionstatement This workwassupportedbyHRAPharma. Funding received researchgrantsfromNovartis. and onspeakerpanelsforNovartisHRAPharma.JBFChave Pharma. JBhasparticipatedinAdvisoryBoardsforAtterocorandShire sponsored byHRAPharma.FChasreceivedconsultancyfeesfrom (Nancy), M Zalzali(Reims). (Toulouse),D Vezzosi AViard(Reims),Villeneuve(Orléans),GWeryha Tessier (Limoges),FTrulli (Villejuif), CVackrine (Montbrison), P M (Besançon), ASmagala(Colmar), E Sonnet(Brest),RTeissier (Brest), M ASchletzer(Laval),SSchneebeli (StPierredelaRéunion),FSchillo M Saraval-Gross(Amiens),JSarfati (Kremlin-Bicêtre),JSavel(Pessac), (Niort), YReznik(Caen),JLSadoul(Nice),SSalenave(Kremlin-Bicêtre), C Pillegrand(Bondy),LPotton(Grenoble),GRaverot(Bron),MRodes G Petit-Aubert(LeChesnay),APerrin(Roanne),MPhilippon(Marseille), (Pessac), SOudard(Paris),Papadopoulou(Bobigny),J-MPetit(Dijon), (Suresnes),NNéri(Nanterre),PNiccoli(Marseille),MLNunes B Néraud M Moret(Bron),NMorlet-Barla(Marseille),HNarbonne Bénite), BMignot(Besançon),SMillot(Mulhouse),IMorange(Marseille), M Marty(Pessac),PMeliani(Mayotte),SMenon(Rouen),BMestre(Pierre- (Villejuif),AMaisin(Paris),J-CMaiza(StPierredelaRéunion), C Lunogo Léonard(Arras), LLin(LaTrinité, Martinique),FLuca(Strasbourg), F M LeBras(Nantes),A-CGuillou(Lille),CPommelet(Cayenne), (Beauvais), ELandau(Nantes),CLautridou(Paris),HLefebvre(Rouen), (Kremlin-Bicêtre), VKerlan(Brest),YKhalfallah(StEtienne),GLambrey A Guilhem (Montpellier),MJoubert(Caen),CJublanc(Paris),PKamenicky Guiheneuf(Bois-Guillaume),LGuignat(Paris),MGuigui(Trévenans), C G Gravis(Marseille),LGroza(Metz),FGrunenberger(Strasbourg), (Rennes), S Genc (Paris), EGhanassia (Sète),J-JGirard(Loches), F Galland J ElFarkh(Aubenas),GFaure(Niort),PFinichel(Nice),NGaits(Tarbes), Longeras (Clermont-Ferrand),EDutertre(Montpellier),HDuRostu(Rézé), (Monaco), CDoCao(Lille),BDonadille(Paris),MDolz(Brest),PDubray- (Valenciennes), TDeneuville(Paris),RDesailloud(Amiens),GDiPietro Bellaton (Gleizé),BDelemer(Reims),MDeMenthon(Paris),VDegros (Lille), A-LCoulon(Grenoble),FDeBoisvilliers(Montpellier),ADecker- (Périgueux), R Cohen (St Denis), C Collet-Gaudillat (Le Chesnay), C Cortet delaRéunion),JChatelin(Nancy),CClavel(Toulouse),(St Pierre CCoffin Martinez (StJeandeVerges), CChambre(Bobigny),MChardonnet D Buliga(StMalo),PCabaret(Lomme),Caron(Toulouse), MCerro- (Paris), CBremont-Weill (Paris),LBricaire (Paris),TBrue(Marseille), (Bron), NBourcigaux(Paris),CBourquard(LePuy-en-Velay), L Bouys (Villejuif), JBertherat(Paris),ABoehna(Mulhouse),FBorson-Chazot Benamo(Avignon), ABennet(Toulouse), ABerdelou (Bobigny), E (St DenisdelaRéunion),MBatisse-Lignier(Clermont-Ferrand),CBaudry (Vannes), G Arnault JBacchetta(Bron),EBaechler-Sadoul (Nice),F Bakiri (Béziers), A-S Arbey (Lons-le-Saunier), F Archambeaud (Limoges), Use Programme:JAbeillon(Bron),CAjzenberg(Créteil),J-MAndrieu syndrome Ketoconazole inCushing’s Downloaded fromBioscientifica.com at09/27/202101:23:58AM 178 www.eje-online.org :5 457 via freeaccess European Journal of Endocrinology www.eje-online.org References 14 13 12 11 10 5 9 8 7 6 4 3 2 1 Clinical Study Garcia Rodriguez LA,Duque A,Castellsague J,Perez-Gutthann S& Lewis JH, Zimmerman HJ,Benson GD&Ishak KG.Hepatic associated with Greenblatt HK &Greenblatt DJ.Liverinjury Yan JY, Nie XL,Tao QM, Zhan SY&Zhang YD.Ketoconazole &Winter JS.Couch RM, Muller J,Perry YS Kineticanalysisof Lo Re V3rd,Carbonari DM,Lewis JD,Forde KA,Goldberg DS, Dandona P, Mohiuddin J&Prentice HG.Ketoconazoleand Bradbrook ID, Gillies HC,Morrison PJ,Robinson J,Rogers HJ Angeli A &Frairia R.KetoconazoletherapyinCushing’s disease. 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