β β β Key words β β I
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
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 0 0 0.±..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
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
Administration Meal Subjectivesymptom Medicalexamination Weight Bloodpressure, pulserate,temp -leadecg Laboratorytests ) Plasmadrugconcn Day- - - 9- - 0 Table. Scheduleofrepeatedadministrationstudy Day Day- Timeafterstartofadministration 0 - - 0 ) 5 0 - - 0 Day7 Urinarydrugconcn - -0 0- - 0- ) 0- Administration Meal Subjectivesymptom Medicalexamination Weight Bloodpressure, pulserate,temp -leadecg Laboratorytests Plasmadrugconcn Urinarydrugconcn Day- Day Timeafterstartofadministration Day 0 Day Day Day Day 9 - - 0 5 0 - - 0 0 7 9 ) ) ) 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 - 0-0- - - β β µ β β β β β β
ng ml,000 Fasting Fed H- Plasma concentration 00 0 Mean S.D. n 0 0 7 9 Time h Fasting n Fed n H- H- Cmax ng ml 09.9. 59.5 7.5 5... 0.0 Tmax h. 0..5 0..... t h. 9. 7.7.. 7.7 7.5. AUCinf ng h ml,.7 70. 7,055.,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
ng ml 0,000 Plasma concentration,000 00 0 -S 0 ml 0 ml 0 ml 0 ml Mean S.D. n 0 0 7 9 ng ml Time h 0,000 -S H- Plasma concentration,000 00 0 0 ml 0 ml 0 ml 0 ml Mean S.D. n 0 0 7 9 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- 09.9. 59.5 7.5..,00. 0.,07.7 0.0,. 9.0,.5.0,79... 0..5 0.. 0..0....7.0. 0.. 0.5. 9. 7.7.. 5.....7.. 9.. 0.9.0,.7 70. 7,055.,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
ng ml 0,000 -S H- 0 ml 0 ml,000 Plasma concentration 00 0 Mean S.D. n 7 0 7 9 0 9 0 Day 5 7 9 0 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- 97. 5.9,..,9.9 0.5,.0.9,0.0 9.,9..,50.7 57.,5.7 9..0 0..0 0.0.9 0.7. 0.5.9 0.7. 0.5...0.0. 0. 9.0. 9.0 5. 7.. 0,5.,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
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..±..±..± 9. 7.7±..± 7.7 7.5±.,.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±..± 7. 9.5±.0.9± 7.7 7.±., ± 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
Table9. TroughplasmaconcentrationdaysafteradministrationofItraconazoleoralsolution -S Day 00mg H- -S Day 00mg H-. ±. 9.5 ±5.5 9. ±5.. ±9.. ±. 77. ±7.0.5 ±.9 7.0 ±00.9. ±.. ±79.9 9. ±. 99.9 ±.9 5 77.9 ±9.0 59.0 ±9.9 5 0. ±.5,5. ±5.5 9. ±.7.9 ±. 55. ±.,. ±7. 7. ±9. 70. ±. 7. ±9.,. ±5. 79.5 ±. 7.5 ±7.5 75. ±5.,0. ±9. 9 9. ±.5 790.5 ±5.7 9 5.7 ±5.0,0. ±5. 0.9 ±9.9 95.7 ±. 0 5.7 ±7.,0. ±5.7. ±90. 9. ±0. 77.9 ±0.7,7. ±5. 5.5 ±95. 9. ±.7,0. ±.,0. ±. 7.5 ±0. 977. ±9.,0. ±.0,507. ±7. µ µ µ µ β β β β β β β β
ng/ml 50 00 50 -S alone -S meprazole Plasma concentration 00 50 00 50 00 50 Mean S.D. n 0 0 7 9 Time h ng ml 50 H- -S alone 00 -S meprazole 50 Plasma concentration 00 50 00 50 00 50 0 Mean S.D. n 0 7 9 Time h -S alone n -S meprazole n Janssen Pharmaceutica data H- H- Cmax ng ml Tmax h t h AUC ng h ml 7.. 7.9.. 9.0 7.9 7.. 0.5. 0.5. 0.5..0 9..9.9.7 9..0..0,5 5 5,5,0,979 5,5,09 Mean S. D. Fig.5. EfectofmeprazoleonplasmaconcentrationofItraconazoleoralsolution. β β β β
β in vitro in vivo β β β