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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 5 5.1±5.1,37 Japanese 75.±5.5,3 1, 5.±3.,3 placebo 1.±5. 1,37 17.±5. 16.±. 176.7±5.5 17.±7.1 173.5±.5 17.1 171.5 177. 173.1 17.6 163.3,1. 155.5,15.5 167.,1. 156.,1. 15.,13.6 6.±5.5 6.3 56.,73. 1.1±1. 1 1.,3.3 6.3±1. 5. 51.,7. 1.6±. 1.1 1.6,.7 6.5±5.3 6. 56.,75.7.6±1.1. 1.,.7 6.±.6 7.1 56.,1. 3.±..1 1.,. 61.6±6.6 61. 5.,75.5.±1.3.6 1.5,.5 1.6±16.1 115.6±11.5 1.±1. 11.6±.5 11.±1.1 1 11 133 117 113.5,131,1 16,13 16,13 17,15 Caucasian 5 placebo 3 3.3±5.6 3.7±6.1 3 3,3,36 17.7±5.7 175.6±6. 17.5 173.5 17.5,1.1 171.,1. 77.±6.1 7.7±5.7 7 7. 67.5,. 6.,..±.3.±1....,..,5.6 111.±17. 1.3±. 1 13 3,1,11 (B)Multiple-dosestudy dose(mg) 5 7days nonelderly 5 7days nonelderly placebo 5 7days elderly 5 7days elderly placebo n 3 3 Age (yr) 3.±.5 3,7.7±3. 1,7 7.±.5 7 67,73 7.3±3.5 7 67,7 Height (cm) 16.5±3.7 16.5 16.,177.5 16.±7.5 171.3 15.,17. 157.5±7. 16. 1.7,165. 16.7±.7 16.6 155.,17.3 Bodyweight (kg) 6.6±5.1 63.7 56.,71.6 63.3±7.3 61. 57.1,71. 6.±.5 56. 5.6,76.5 6.3±1.3 6. 5.,.6 BMI (kg/m ) 1.±1..6 1.3,.6.±3.. 1.,.3.±.5 3. 1.,7. 5.6±. 6.5.,7. Ccr(Cockcroft) (ml/min) 11.±16. 113 3,13.±15.,11.1±1.1 5 7,15 1.±3.3 6 7,15
(A)Single-dosestudy Hospitalization Dose Subjectbackground Investigator sexamination Height Bodyweight BMI Temperature,bloodpressure,pulserate 1-leadelectrocardiogram Clinicallaboratorytest Immunologicaltest Pharmacokinetic Monitoring Drugtest(urine) Table. Studyscheduleinthe(A)singleand(B)multiple-dosestudies Hematology,blood biochemistry,urinalysis Ccr Plasma 1) Saliva ),3) Urine ) Screening Day- <_ - - 1 1 3 Folow-up 1) Bloodsamplescolected:immediatelybefore(timezero),.5,.5,1,1.5,,3,,,1,,36,,6,and 7h ) Salivarysamplescolected:immediatelybefore(timezero),1,,3,,,1,andh 3) Salivarysampleswerecolectedfrom subjectsadministeredlvfx5mg. ) Urinarysamplescolected:-,,,, 1,1,,and 7h (B)Multiple-dosestudy Hospitalization Dose Subjectbackground Investigator sexamination Height Bodyweight BMI Temperature,bloodpressure,pulserate 1-leadElectrocardiogram Clinicallaboratorytest Immunologicaltest Pharmacokinetic Monitoring Intestinalflora 3) Drugtest(urine) Hematology,blood biochemistry,urinalysis Ccr Plasma 1) Screening Day- <_ - - 1 1 3 5 6 7 1 Folow-up 1 Urine ) ) ) 1) Bloodsamplescolected:day1;immediatelybefore(timezero),.5,.5,1,1.5,,3,,,and1h day 6;immediatelybefore(timezero)and1.5h day7;immediatelybefore(timezero),.5,.5,1,1.5,,3,,,and1h day;and36h day;and6h day1;7h ) Urinarysamplescolected:day-1;- h days1and7;,,, 1,and1 h 3) OnlynonelderlyJapanese.Fecessamplingwasdoneoncewithineachinterval. ) Asubjecthavingnobowelmovementwashospitalizedinthreedaysatmaximum.
5 mg (n ) 5 mg (n ) Plasma concentration ( g/ml) 15 1 5 75 mg (n ) 1, mg (n ) 6 1 1 3 36 5 6 66 7 Time (h) Fig.1. LVFX plasma concentration aftersingle-dose oraladministration to Japanese subjects (). Table3. LVFXpharmacokineticparametersinsingle-dosestudy Dose (mg) n Cmax (μ g/ml) tmax (h) AUC 7h (μ g h/ml) AUC inf (μ g h/ml) t1/ (h) CLt/F (L/h) Vdz/F (L) CLr (L/h) 5 Japanese mean SD 3.7.3 1.1.3 1.77.1 1.5. 7. 1.7 11.6 1.6 1.7 16.6.1 1.5 5 Japanese Caucasian mean SD mean SD 7.35.1.61 1.1 1..7 1..5 57.6.7 7.3.3 5..6 7.1.3.6.1..6. 1.3 1.7 1. 13.6 36. 1. 6. 7. 1.1.. 75 Japanese mean SD 1.53 3.3 1.3.5 3.15.5 3.3.6. 1.5.1 1. 116. 6. 7.. 1, Japanese mean SD 15.37.63 1..5 111.61 1.16 111.3 1.1 7.5..1 1.1. 1.5 7.1 1.
(A) 15 Y.13X 1.1 Cmax ( g/ml) 1 5 5 5 Dose (mg) 75 1, (B) 15 1 Y.3X 1.17 AUC 7 h ( g h/ml) 6 3 5 5 Dose (mg) 75 1, Fig.. TherelationshipbetweenLVFXpharmacokineticparametersversusdoseafter single-doseoraladministrationtojapanesesubjects(x=dose,y=parameter). (A)Cmax,(B)AUC 7h α β α β β
(A) 1 Cumulative urinary excretion ( of dose) 6 5 mg (n ) 5 mg (n ) 75 mg (n ) 1, mg (n ) 6 1 1 3 36 5 6 66 7 Time (h) (B) Urinary concentrationg/ml 1,6 1, 1, 1, 6 5 mg (n ) 5 mg (n ) 75 mg (n ) 1, mg (n ) 1 1 7 Time (h) Fig.3. (A)CumulativeLVFX urinaryexcretionand(b)lvfx urinaryconcentrationafter single-doseoraladministrationtojapanesesubjects(). II µ µ β β β
1 1 Saliva (n ) Plasma (n ) Concentration ( g/ml) 6 1 16 Time (h) Fig.. LVFXsalivaryandplasmaconcentrationafter5mgsingle-doseoraladministration tojapanesesubjects(). Plasma concentration ( g/ml) 1 6 Nonelderly (n ) Elderly (n ) 7 6 1 1 16 1 16 Time (h) Fig.5. LVFXplasmaconcentrationin5mgmultiple-dosestudy(). β µ µ µ
(A)Day1 Group n Table. LVFXpharmacokineticparametersinmultiple-dosestudy Cmax (μ g/ml) Ch (μ g/ml) tmax (h) AUC h (μ g h/ml) LVFX5mg mean 6..37 1.7 3.36 nonelderly SD 1... 3.76 LVFX5mg mean 6..71 3.3 5.75 elderly SD...7.1 (B)Day7 Group n Cmax (μ g/ml) Ch (μ g/ml) tmax (h) AUC h (μ g h/ml) t1/ (h) CLt/F (L/h) Vdz/F (L) CLr (L/h) LVFX5mg mean 6.3.7 1..67. 1. 136.6 7. nonelderly SD 1.15.15. 6.6. 1.5 36.. LVFX5mg mean 7.1.1.1 67..5 7.6 1. 5.5 elderly SD..3.5 1.7 1. 1.1.6 1.1 µ µ µ µ µ µ µ µ µ µ µ µ Clostridium difficile C. difficile III µ µ
1 1 Aerobes (log CFU/g) 6 1 3 5 6 Mean number of aerobic bacteriae (n ): Enterobacteriaceae, NFGNR, Staphylococcus, Streptococcus, Enterococcus, Bacillus, Corynebacterium, Yeast, Total aerobes 1 1 Anaerobes (log CFU/g) 6 1 3 5 6 Mean number of anaerobic bacteriae (n ): Bacteroidaceae, Fusobacterium, Lecithinase ( ) Clostridium, Lecithinase ( ) Clostridium, Veillonella, Megasphaera, Bifidobacterium, Eubacterium, Peptococcaceae, Lactobacillus, Total anaerobes Fig.6. ImpactsofLVFXadministrationonintestinalflorainnonelderlyJapaneseinmultiple-dose study. Abscissa 1:daysbeforedose-day1 :day1 day3 3:day day6 :day7 day 5:day1 6:day
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