日本化学療法学会雑誌第54巻第S-1号

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1 Key words β β

2 Table. CmaxandAUCinsingleintravenousinjectionstudy ITCZAdministration (mg) n Cmax(ng/mL) ITCZ OH-ITCZ AUC( )(ng hr/ml) ITCZ OH-ITCZ 5 7.7± ±.,959.7±.9,78.± 557.,59.±.9.± 5. 5,8.7± 97.,77.±,7.,.7±, ±. 7,.±,79.,.5±9,. Mean±S.D. [JanssenPharmaceuticalInternalData] Table. CmaxandAUCinrepeatedintravenousinjectionstudy ITCZAdministration (mg) n Cmax(ng/mL) ITCZ OH-ITCZ AUC( )(ng hr/ml) ITCZ OH-ITCZ,98.±.7,.±8. 5,.±,598.,98.5±,97.5,57.7±58.9,8.5±58.9,8.5±7,8.,9.±9,85. Mean±S.D. [JanssenPharmaceuticalInternalData] I

3 StudyPeriod ITCZInjectiontreatment Priorto Injections Examination andobservation ITCZInjection ClinicalManifestation FungalTest SerologicTestforFungi GeneticTestforFungi EndoscopicExamination DiagnosticImaging (X-ray,CTscan,etc) HematologicalTest/ BloodBiochemicalTest UrineTest hrcreatinineclearance Test Cardiogram AdverseEvent Blood Sample to Testfor AmountofMedication in Plasma StudyPeriod Examination andobservation ITCZCapsule Administration Table. Examination/observationandimplementation Day Day Day Day Day Injection Day Week Week Week Week Twice/dayTwice/day 滑害害害害害 Once/day 害害害害害葛 滑害害害害 SpecimenColectionPeriod 害害害害葛 滑害害害害害害害 Twice 害害害害害害害葛 滑害害害害害害害害害 Asnecessary 害害害害害害害害害害葛 Day5 Initial Day 滑害害害害 AccordingtoSymptoms 害害害害葛 滑害害害害 AccordingtoSymptoms 害害害害葛 滑害害害害害害害害害害害害害害害害害害害害害害害害葛 Week Week Week Week Week Week8 CapsuleAdministration Week Week Week Week8 Week Week Week Week ITCZCapsuleAdministration 滑害害害害害害害害害害害害害害害害 Twice/day 害害害害害害害害害害害害害害害害害葛 ClinicalManifestation FungalTest SerologicTestforFungi EndoscopicExamination DiagnosticImaging (X-ray,CTscan,etc) HematologicalTest/ BloodBiochemicalTest UrineTest Cardiogram AdverseEvent Blood Sample to Testfor AmountofMedication in Plasma 滑害害害害害害害害害害害 SpecimenColectionPeriod 害害害害害害害害害害害葛 滑害害害害害害害害害害害害 AccordingtoSymptoms 害害害害害害害害害害害害葛 滑害害害害害害害害害害害害 AccordingtoSymptoms 害害害害害害害害害害害害葛 Days AfterFinal Administration 滑害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害害葛 required HematologicalTests:WBCcount,RBCcount,hemoglobin,hematocrit,plateletcount,diferentialcountofleukocytes BloodBiochemicalTests:totalbilirubin,ALP,AST(GOT),ALT(GPT),LDH,γ-GTP,totalprotein,albumin,glucose,totalcholesterol,triglyceride,CK,BUN,creatinine,ureanitrogen,Ca,Na,K,Cl,CRP UrineTests:sugar,protein,urobilinogen,sediment

4 Table. Totalefectcriteria TotalEfect(DeepMycosisexcludingAspergilomaandAsymptomaticPulmonaryCryptococcosis) Efective:Whenclinicalsymptomsofdeepmycosisdisappear/improve,andnoresultsfrom mycologicandserologictests,orendoscopyand diagnosticimaging(x-ray,ct,etc.),indicateincreasing/worsening,andatleastoneofthefolowingpointsapply: )Mycologicaltestsevaluatefungusasdisappeared/presumeddisappearedorreduced. )Fungalserologicaltestsreturnnegativeorimprovedresults. )Thedegreeofimprovementassessedbyendoscopyanddiagnosticimagingindicatesymptomshavedisappearedorimproved. NoEfect:Whentotalefectsarecategorizedneitherasefectivenorimpossibletoevaluate. ImpossibletoEvaluate:Whentheimprovementofclinicalsymptomsisassessedasimpossibletoevaluate,orclinicalsymptomsfordeepmycosisaredeterminedtohavedisappeared/improved,butfungalserologicaltestsandendoscopyanddiagnosticimagingalindicate thatimprovementassessmentisimpossible. TotalEfect(Aspergiloma) Efective:Whenclinicalsymptomsofaspergilomadisappear/improve,andnoresultsfrom mycologicalandserologicaltests,orendoscopy anddiagnosticimaging(x-ray,ct,etc.),indicateincreasing/worsening,andatleastoneofthefolowingpointsapply. )Thedegreeofimprovementassessedbydiagnosticimagingindicatesymptomshavedisappearedorimproved. )Mycologicaltestsevaluatefungusasdisappeared/presumeddisappeared. NoEfect:Whentotalefectsarecategorizedneitherasefectivenorimpossibletoevaluate. ImpossibletoEvaluate:Whenimprovementofclinicalsymptomsisassessedasimpossibletoevaluate,orclinicalsymptomsforaspergiloma aredeterminedtohavedisappeared/improved,butthedegreeofimprovementevaluatedbyimagingisunchangedorisimpossible toevaluate,themycologictestsindicatedecreased/unchangedorimpossibletoevaluate,andfungalserologicaltestsarenotassessedasworsening. TotalEfect(AsymptomaticPulmonaryCryptococcosis) Efective:Whenresultsfrom mycologicalandserologicaltests,andendoscopyanddiagnosticimaging(x-ray,ct,etc.)donotindicate increasing/worsening,andatleastoneofthefolowingpointsapply: )Mycologicaltestsevaluatefungusasdisappeared/presumeddisappearedorreduced. )Fungalserologicaltestsreturnnegativeorimprovedresults. )Thedegreeofimprovementassessedbyendoscopyanddiagnosticimagingindicatesymptomshavedisappearedorimproved. NoEfect:Whentotalefectsarecategorizedneitherasefectivenorimpossibletoevaluate. ImpossibletoEvaluate:Whentheimprovementofclinicalsymptoms,mycologicaltestresults,fungalserologicaltestresults,andendoscopy anddiagnosticimagingresultsarealassessedasimpossibletoevaluate. ITCZ Injection: 5 Subjects Safety analysis population: 5 Subjects Excluded from efficacy analysis population: Subjects Incompatible with basic assessment Impossible to evaluate total effects 7 Exclusion criteria/violation of concomitant medication Poststudy disqualification ) Insufficient administration ) After the study had begun, an unanticipated conflict became apparent, and administration was discontinued. Efficacy analysis population: Subjects ) Aspergillosis 9 Candidiasis 7 Cryptococcosis 5 ) Some subjects presented with both pulmonary cryptococcosis and esophageal candidiasis, and were included in both groups. Fig.. Numberofsubjectsforanalysis.

5 Gender Age(years) Weight(kg) Diagnosis Underlying Medical Condition Useof antifungal medication startedwithin weeks priortoinitial administration ofstudy medication Male Female Disease Subjects Mean±S.D. (Min,Max) < 5 5 Mean±S.D. (Min,Max) ChronicNecrotizingPulmonary Aspergilosis InvasivePulmonaryAspergilosis Aspergiloma AspergiloticOsteomyelitis AspergilusBrainAbscess Candidemia DisseminatedCandidiasis PulmonaryCandidiasis EsophagealCandidiasis UrinaryCandidiasis PulmonaryCryptococcosis Table5. Patientprofile Aspergilosis ±.9 (,79) 7 9.±9.7 (.8,9.) 9 Candidiasis 57.±.5 (,8) 5.±. (7.5,9.) Cryptococcosis.5±. (,77) 5.±. (.5,7.5) Deep Mycosis ) ±5.8 (9,79) 5.9±9.9 (.7,9.8) Total ±5.7 (9,79) 5 5.9±. (.8,7.5) DeepMycosis ) None Existing 5 Main Disease ) None Existing Blood/Hematopoietic Respiratory Colagen SolidMalignantTumor ObsoletePulmonaryTB Diabetes 7 8 Fluconazole Medication ) AmphotericinB 7 5 Miconazole Reasonfor InsuficientEfects 9 change ) SideEfects ) Deepmycosisthatdoesnotfulfildiagnosticcriteria, ) Includesduplications II

6 Table. Eficacy Disease Diagnosis Aspergilosis InvasivePulmonaryAspergilosis ChronicNecronicPulmonaryAspergilosis Aspergiloma AspergiloticOsteomyelitis Candidiasis Candidemia DisseminatedCandidiasis PulmonaryCandidiasis EsophagealCandidiasis UrinaryCandidiasis Cryptococcosis PulmonaryCryptococcosis Total E/SE * ITCZInjection Evaluation 7/7 / 5/8 / / /7 / / / / / /5 /5 5/9 ER ** E/SE * /9 / 5/8 / / 5/7 / / / / / 5/5 5/5 / * E/SE:Eficacy/SubjectsEvaluated, ** ER:EficacyRate, *** CI:ConfidenceInterval FinalEvaluation ER ** 95%CI *** 57.9 [ ] 5. [.8-9.].5 [.5-9.5] 5. [.8-88.] [.5-] 7. [9-9.] 5. [.-98.7] [ -97.5] [.5-] [5.8-] [.5-] [7.8-] [7.8-] 7.7 [8.-8.] Disease Diagnosis Aspergilosis InvasivePulmonaryAspergilosis ChronicNecronicPulmonaryAspergilosis Aspergiloma AspergiloticOsteomyelitis Candidiasis Candidemia DisseminatedCandidiasis PulmonaryCandidiasis EsophagealCandidiasis UrinaryCandidiasis Cryptococcosis PulmonaryCryptococcosis Total Table7. Itemizedevaluationresultsfrom finalevaluation Improvementof ClinicalSymptoms IR ) /9 / /8 / / 7/7 / / / / / / / / Mycological Results DR ) /7 / / / / / / / / / / / Fungal Serological Results IR ) 9/8 / /7 / / / / / / / / / / Improvementof Endoscopyand Imaging ) Improvement=(numberofsubjectswithdisappearance+ numberofsubjectswithimprovementofsymptoms)/(subjectsevaluated,ex cludingsubjectsimpossibletoevaluate) ) Disappearance=(numberofsubjectswithdisappearanceorassumeddisappearance)/(subjectsevaluated,excludingsubjectsimpossible toevaluate) ) Improvement=(numberofsubjectswithanegativeresult+ numberofsubjectswithanimprovedresult)/(subjectsevaluated,excluding subjectsimpossibletoevaluate) IR ) 8/9 / /8 / / / / / / 5/5 5/5 /

7 Table8. Eficacyforspecificfungusinfinalevaluation UnderlyingFungus Aspergilusfumigatus Aspergilustereus E/SE * /7 / ER ** %CI *** [8.-9.] [.5-] Candidaalbicans ) /5. [.7-9.7] Candidaglabrata ) / [5.8-] Candidatropicalis / [.5-] Cryptococcusneoformans 5/5 [7.8-] * E/SE:Eficacy/SubjectsEvaluated, ** ER:EficacyRate, *** CI:ConfidenceInterval ) OnesubjectwhohadCandidaalbicansandCandidaglabratais includedinbothresults. Table9. Eficacyformaindiseases Disease Underlying Circulatory Respiratory Colagen SolidMalignantTumor Obsolete Pulmonary Tuberculosis Diabetes ER E/SE * ** /5 / / / /5 / Aspergilosis 95%CI ***. [.7-9.7].7 [.-95.7] [.5- ] [.5- ]. [ ].7 [ ] ER E/SE * ** / / / Candidiasis 95%CI ***.7 [ ] [.5- ] 5. [.-98.7] ER E/SE * ** / / / * E/SE:Eficacy/SubjectsEvaluated, ** ER:EficacyRate, *** CI:ConfidenceInterval Cryptococcosis 95%CI *** [.5- ] [5.8- ] [.5- ] E/SE * 5/8 5/7 / / /5 / ER ** Total 95%CI *** [.5-9.5] [9.-9.] [9.8- ] [ ] [ ] [9.-99.] % 8 Impossible to evaluate Worsened Unchanged Clinical improvement Improved Disappeared Pre 8 W ITCZ Injection ITCZ Capsule Administration n Fig.. Improvementinclinicalsymptoms.

8 Body Temperature C Mean S.D. t-test vs. Preadministration p.5 p.. Pre D W ITCZ Injection W ITCZ Capsule Administration 8 W n mg/dl 8 Mean S.D. t-test vs. Preadministration p.5 p. CRP Pre 8 W D W W ITCZ Injection ITCZ Capsule Administration n Fig.. ChangeinbodytemperatureandCRP. β β β

9 ng/ml, Plasma Concentration of Medication 5,,,,, ITCZ OH-ITCZ Mean S.D. Pre W D W W ITCZ Injection ITCZ Capsule Administration n Fig.. Changeinplasmaconcentrationofmedication(subjectsreceivingmgITCZ/injection). ng/ml, Plasma Concentration of Medication 5,,,,, ITCZ mg/injection, mg/capsule ITCZ mg/injection, mg/capsule OH-ITCZ mg/injection, mg/capsule OH-ITCZ mg/injection, mg/capsule Mean±S.D. Pre D W W ITCZ Injection ITCZ Capsule Administration mg/ capsule n mg/ n capsule Fig.5. Changeinplasmaconcentrationofmedication(subjectsweighinglessthan5kgwhoreceived mgofitczinjection). W

10 Table. MICvalueforITCZclassifiedbyunderlyingfungus IsolatedFungus Aspergilusfumigatus Aspergilusniger Aspergilustereus Candidaglabrata Candidaalbicans Candidatropicalis Cryptococcusneoformans Cases 5 5 MIC(μ g/ml) Min Max orless..5.5.orless. III

11 Table. Occurenceofadvancereactionclassifiedbygrade Grade Severe Moderate Mild AdverseEvent System organclass Cases Cases Cases PneumoniaNOS InfectionandGiardiasis. Thrombocytopenia BloodorLymphDisorder AnemiaNOS. Hyperkalemia Metabolicor NutrientDisorder. Hypertriglyceridemia. LossofAppetiteNOS 7.8 Anorexia..7 7 Hypokalemia. Anxiety MentalDisorder. DepressionSymptoms. LossofSensation NervousSystem Disorder. Drowsiness. Tremor Headache. Dysphonia 5.9 Dizziness. AbnormalPalate. RetinalHemorhage OcularDisorder. CongestiveHeartFailure HeartDisorder. RightBundleBranchBlock. BradycardiaNOS HeartFailureNOS Palpitation. TachycardiaNOS. ValvularCardiacDiseaseNOS.. AngiopathyNOS CirculatoryDisorder. Erubescence. Coughing Respiratory,Thoracic, ormediastinaldisorder. Dyspnea. LungHemorhage Nausea GastrointestinalDisorder. GastritisNOS. GastroduodenalUlcer. GastricDiscomfort DiarheaNOS. Flatulence. GastrointestinalDyskinesiaNOS. Indigestion.. EpigastricPain. EnlargedLingualPapilaNOS. LooseStool. AbdominalDiscomfort. AbdominalDistension Constipation. VomitingNOS (Continued)

12 . LiverDamageNOS HepatobiliaryDisorder 5.9 Pruritus Dermalor HypodermalDisorder. Erythema.. Eczema. SystemicPruritus. Rash. DrySkin. SwelingofSkin. MuscleRigidity Musculoskeletalor ConnectiveTissue Disorder. SwelingNOS. BackPain Hematuria RenalorUrinaryDisorder 5.9 AbnormalUrineNOS. UrinaryComplications. FrequentUrination.. Chils SystemicDisorderor SiteReactiondueto injection.. Dysesthesia.. Malaise. DryMouth LocalReactionNOS. LocalPain Fever.. SwelingNOS. PeripheralSweling. Asthenia 5.9 CRPIncrease ClinicalTests AST(GOT)Increase 9. ALT(GPT)Increase. IncreaseinAmmonia. DecreaseofHematocrit. DecreaseofHemoglobin 7.8 Increaseofγ -GTP(γ -GP).. IncreaseinBloodPressure. DecreaseinPlateletCount. IncreaseinSerum AI-P DecreaseinSerum Potassium.. DecreaseinSerum Cholesterol. DecreaseinSerum Sodium. IncreaseinSerum Bilirubin IncreaseinSerum LDH. IncreaseinEsinophilPercentage. DecreaseinEurythorcytes DecreaseinLeukocytes IncreaseinBodyWeight. CastinUrine GlucoseinUrine. BloodinUrine. ProteininUrine. DecreaseinUrineVolume. Self-InflictedWound Accident,Poisoning,or TreatmentComplication Table.(Continued)

13 Table. PlasmaconcentrationofITCZandoccurenceofadvancereactionatfinalevaluation FinalEvaluationPlasma ConcentrationofITCZ (Median:,79.ng/mL) GroupwithHighConcentrationofITCZ (abovemedian) GroupwithLowConcentrationofITCZ (belowmedian) Total Cases 5 9 Cases 7 7 Mild Grade ) Moderate Cases Cases Severe ) Whenonesubjectpresentedwithmorethanoneadvanceevent,themoreseverecasewasdocumented... Total Cases Table. Influenceofmedicationonrenalfunction CreatinineClearance(mL/min) TestPeriod RenalFunction Classification Subjects Priorto Administration After Administration Pairedt-test weekfolowing ITCZInjection Normal ModeratelyAbnormal 5.±8..9± ± 8. 8.±9. 7.±5. 7.±.5 p=. p=.8 p=. weeksfolowing ITCZInjection Normal ModeratelyAbnormal 9.9±.8 9.9± 7..±..±. 75.±.7 5.±.9 p=.7 p=. p=. CompletionofITCZ CapsuleAdministration Mean±S.D. BUN(mg/dL) TestPeriod RenalFunction Classification Subjects Priorto Administration After Administration Pairedt-test weekfolowing ITCZInjection Normal ModeratelyAbnormal.±.8 5.±.5 7.± ±..± 5. 7.± 5.5 p=. p=.77 p=.95 weeksfolowing ITCZInjection Normal ModeratelyAbnormal 5.±.8.7±. 7.±7..±..9±.9 5.7± 5.8 p=.9 p=.88 p=.7 CompletionofITCZ CapsuleAdministration Normal ModeratelyAbnormal 8.7±.8.±. 7.±7..5±.7.±..±.9 p=.9 p=.8 p=.89 Mean±S.D. Serum Creatinine(mg/dL) TestPeriod RenalFunction Classification Subjects Priorto Administration After Administration Pairedt-test weekfolowing ITCZInjection Normal ModeratelyAbnormal 7.7±..7±..±..7±..7±..9±. p=.9 p=.8 p=.9 weeksfolowing ITCZInjection Normal ModeratelyAbnormal 5 5.7±..7±..9±..±..±..9±. p=. p=. p=. weekfolowing ITCZ CapsuleAdministration Normal ModeratelyAbnormal 8.±..7±..9±..±..±..7±. p=. p=. p=. Mean±S.D.

14 Item Tested Table. Significantchangesinclinicalvaluesbeforeandafteradministration Preadministration- CompletionofA n Median( Min,Max) Hematological LeukocyteCount(/μ L) ITCZCapsuleAdministration - 95 (- 5,8,,8) p=. Test Rod-shapedCels ITCZCapsuleAdministration (, 9) p=.9 Biochemical BloodTest TotalCholesterol(mg/dL) Tryglyceride(mg/dL) TotalProtein(g/dL) UricAcid(mg/dL) Creatinine(mg/dL) TotalBilirubin(mg/dL) Sodium(mEq/L) Potassium(mEq/L) Chloride(mEq/L) Calcium(mEq/L) ITCZCapsuleAdministration ITCZCapsuleAdministration ITCZCapsuleAdministration ITCZCapsuleAdministration ITCZCapsuleAdministration ( - ( -. ( -.5 ( -. ( -. ( -.5 ( - 88, - 7, -., -.5, -., 7) ) ).8).) -.,.7) -.,.5). ( -.55, ( -. ( -. ( ( ( -, -.9, -.8,.) ).9) ) - 9,.) -,.7) -.5 ( -.75,.55) t-test p<. p=. p=.95 p=. p=. p=. p=. p=. p=. p=. p=. p=. p=. p=. Candida glabrata β

15

16 Aspergillus Candida Cryptococcus

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