日本化学療法学会雑誌第54巻第S-1号

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みいかやすもと
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1 β β β Key words β β I

2 HP- -CD CHR RHC R R R R CHR R R R R RHC R R R CHR R R R RHC CHR R H CH CH Fig.. Structuralformulaofhydroxypropyl-β -cyclodextrin(hp-β -CD). CH n H β β β β

3 Table-. Dosageandadministration(Singleadministrationstudy) Step Drug(Dosage) Volume Administration n -S(00mg/g) 0mL fastingorfed Placebo(g) 0mL -S(00mg/g) 0mL Placebo(g) 0mL -S(00mg/g) 0mL fasting Placebo(g) 0mL -S(00mg/g) 0mL Placebo(g) 0mL Dosage:-S(Itraconazole:mg/HP-β -CD:g)orPlacebo(HP-β -CD:g) Step Table-. Dosageandadministration(Repeatedadministrationstudy) Drug(Dosage) -S(00mg/g) Placebo(g) -S(00mg/g) Placebo(g) Volume 0mL 0mL 0mL 0mL Administration oncedailyfor daysfasting Dosage:-S(Itraconazole:mg/HP-β -CD:g)orPlacebo(HP-β -CD:g) n 7 7 Table-. Background characteristics(singleadministration study) Table-. Backgroundcharacteristics(Repeatedadministrationstudy) Step n Age Height(cm) Weight(kg) Step n Age Height(cm) Weight(kg) Total.0±..9±.5.±..±.5.±. (0-0) 9.±. 7.9±. 7.9±.9 7.±7. 7.7±5. (.-.) 59.9±.0.±.5.±.5.5±9..9±. (5.-.) Total ±..9±..±. (0-) 7.7±5. 7.±7. 7.±. (.-7.).±5..±9..7±. (5.-77.) Mean±S.D.(Min-Max) Mean±S.D.(Min-Max) II

4 Administration Meal Subjectivesymptom Medicalexamination Weight Bloodpressure, pulserate,temp -leadecg Laboratorytests ) Plasmadrugconcn Urinarydrugconcn Fecaldrugconcn ) Day Freetime Freetime 0 ) Table. Scheduleofsingleadministrationstudy Day 5 Day Timeafterstartofadministration 0 Day 0 Day 7 Day5 9 Folowup ) ) Hematology:WBC,WBCdiferential,RBC,hemoglobin,hematocrit,meancorpuscularvolume(MCV),meancorpuscularhemoglobin(MCH), meancorpuscularhemoglobinconcentration(mchc),plateletcount Bloodbiochemistry:glucose,totalprotein,albumin,A/G,triglyceride,totalcholesterol,Cr,BUN,uricacid,totalbilirubin,directbilirubin, GT,GPT,guanase,lactatedehydrogenase,γ -GTP,ALP,leucineaminopeptitase,creatinekinase,amylase,Na,K,Cl,C-reactiveprotein Urinalysis:specificgravity,sediment,protein,glucose,urobilinogen,bilirubin,pH,occultblood,ketonebody ) Steponly ) Step:fedgrouphavebreakfastat:0 ) weekafteradministration µ β β µ β β

5 Administration Meal Subjectivesymptom Medicalexamination Weight Bloodpressure, pulserate,temp -leadecg Laboratorytests ) Plasmadrugconcn Day Table. Scheduleofrepeatedadministrationstudy Day Day- Timeafterstartofadministration ) Day7 Urinarydrugconcn ) 0- Administration Meal Subjectivesymptom Medicalexamination Weight Bloodpressure, pulserate,temp -leadecg Laboratorytests Plasmadrugconcn Urinarydrugconcn Day- Day Timeafterstartofadministration Day 0 Day Day Day Day ) ) ) Hematology:WBC,WBCdiferential,RBC,hemoglobin,hematocrit,meancorpuscularvolume(MCV),meancorpuscularhemoglobin(MCH), meancorpuscularhemoglobinconcentration(mchc),plateletcount Bloodchemistry:glucose,totalprotein,albumin,A/G,triglyceride,totalcholesterol,HDL-cholesterol,Phospholipid,Cr,BUN,uricacid,total bilirubin,directbilirubin,gt,gpt,guanase,lactatedehydrogenase,γ -GTP,ALP,leucineaminopeptitase,creatinekinase,amylase,Na,K, Cl,C-reactiveprotein Urinalysis:specificgravity,sediment,protein,glucose,urobilinogen,bilirubin,pH,occultblood,ketonebody ) Dayonly ) Day:0-,- ) Day0only β β µ β β β β β β

6 ng ml,000 Fasting Fed H- Plasma concentration 00 0 Mean S.D. n Time h Fasting n Fed n H- H- Cmax ng ml Tmax h t h AUCinf ng h ml, ,055.,7.,57.0,09.0 5,75.7,0. Mean S. D. Fig.. Efectoffoodonplasmaconcentrationafteradministrationofsingledose(00mg)ofItraconazoleoralsolution. β β β β β β β β β β β β β

7 ng ml 0,000 Plasma concentration, S 0 ml 0 ml 0 ml 0 ml Mean S.D. n ng ml Time h 0,000 -S H- Plasma concentration, ml 0 ml 0 ml 0 ml Mean S.D. n Time h -S Cmax ng ml Tmax h t h AUCinf ng h ml 0 ml n 0 ml n 0 ml n 0 ml n H- H- H- H ,00. 0., ,. 9.0,.5.0, , ,055.,7. 7,9.,7.7 9,07.7,7.,9.,7.9,. 7,.9,7.7,.,0.,99.0 Mean S. D. Fig.. PlasmaconcentrationafteradministrationofsingledoseofItraconazoleoralsolution. III

8 ng ml 0,000 -S H- 0 ml 0 ml,000 Plasma concentration 00 0 Mean S.D. n Day administration Time 0 00 h -S Cmax ng ml Tmax h t h AUC 0- ng h ml after 7 days 0 ml n 0 ml n H- H- 0 ml n H- after days 0 ml n H ,.., ,.0.9,0.0 9.,9.., , ,5.,79.,57.,.7,5. 5,0.7 5,. 9,97.,.,07.0 5,99.9,5.,9. 7,57. 59,5.5,99. Mean S. D. Fig.. PlasmaconcentrationdaysafteradministrationofItraconazoleoralsolution. Table5. Adverseeventsfindinginsingleadministrationstudy Step Drug Adverseevents Grade Relationofdrug -S(Fed) Probably -S0mL Rash,Itch -S0mL Rash,Itch Placebo -S0mL Nausea Diarhea Probably Total-bilirubin Direct-bilirubin Probably

9 Table. Adverseeventsfindinginrepeatedadministrationstudy Step Drug Adverseevents Grade Relationofdrug -S0mL Sediment-WBC Placebo Abdominaldispleasure Myalgia Intercostaltenderness Sediment-WBC -S0mL Headache Headache Total-Cholesterol Probably Probably Rightmammarytenderness Probably Placebo Pharyngalgia Cough Pharyngealredness Table7. PharmacokineticsofItraconazoleoralsolutionvs.capsulesinhealthyvolunteersafteradministrationofsingledose(00mg) Cmax(ng/mL) Tmax(h) T/(h) AUC ) (ng h/ml) -S(n= ) fasting fed H- H- 09.9±. 59.5±7.5 5.±..±0.0.±0..5±0..±..±..± ±..± ±.,.7± 70. 7,055.±,7.,57.0±,09.0 5,75.7±,0. -Cap(n= 5) fasting fed H- H- 5.±.5.±0..±0.7 7.±7..±0.9.±0.9.±..0±..± ±.0.9± ±., ± 57, ±,, ±,,77 ±, ) -S:AUCinf,-Cap:AUC0- Mean±S.D. Table. PharmacokineticsofItraconazoleoralsolutionvs.capsulesinhealthyvolunteers(after7or daysadministrationof00mg/day) Cmax(ng/mL) AUC ) (ng h/ml) Tmax(h) -S 7days 97.±5.9 0,5±,79.0±0. -Cap days.±.,±,90.±0. -S/-Cap.. ) -S:AUC0-,-Cap:AUC0- Mean±S.D. β

10 Table9. TroughplasmaconcentrationdaysafteradministrationofItraconazoleoralsolution -S Day 00mg H- -S Day 00mg H-. ±. 9.5 ± ±5.. ±9.. ±. 77. ±7.0.5 ± ±00.9. ±.. ± ± ± ± ± ±.5,5. ± ±.7.9 ±. 55. ±.,. ±7. 7. ± ±. 7. ±9.,. ± ±. 7.5 ± ±5.,0. ± ± ± ±5.0,0. ± ± ± ±7.,0. ±5.7. ± ± ±0.7,7. ± ± ±.7,0. ±.,0. ±. 7.5 ± ±9.,0. ±.0,507. ±7. µ µ µ µ β β β β β β β β

11 ng/ml S alone -S meprazole Plasma concentration Mean S.D. n Time h ng ml 50 H- -S alone 00 -S meprazole 50 Plasma concentration Mean S.D. n Time h -S alone n -S meprazole n Janssen Pharmaceutica data H- H- Cmax ng ml Tmax h t h AUC ng h ml ,5 5 5,5,0,979 5,5,09 Mean S. D. Fig.5. EfectofmeprazoleonplasmaconcentrationofItraconazoleoralsolution. β β β β

12 β in vitro in vivo β β β

日本化学療法学会雑誌第57巻第S-2号

日本化学療法学会雑誌第57巻第S-2号 µ µ Key words µ µ µ I Table1. Subjectprofilesin(A)singleand(B)multiple-dosestudies (A)Single-dosestudy Age (yr) Height (cm) Bodyweight (kg) BMI (kg/m ) Ccr(Cockcroft) (ml/min) Ethnicity dose(mg) n 5 5.1±.,3