Streptococcus pneumoniae S. pneumoniae Moraxella (Branhamella) catarrhalis Haemophilus influenzae Key words Streptococcus pneumoniae β Moraxella (Branhamella) catarrhalis Haemophilus influenzae
Table. SourcesofplasmaTFLXconcentrationdatacolectedinclinicalstudies Pediatricstudy Dosageandsampling Numberof subjects Numberof plasma samples Reference Bacterialpneumonia mg/kgtwicedailyfor days notexceedingmgperdose 7 mg/kgtwicedailyfor days notexceedingmgperdose 5 Bloodsamplescolected.5.5hand h afteradministration Acuteotitismedia mg/kgtwicedailyfor days notexceedingmgperdose 9 mg/kgtwicedailyfor days notexceedingmgperdose 5 Bloodsamplescolected.5.5hand h afteradministration Total I η η ω
Table. Baselinesubjectprofileusedinpopulationphar macokineticanalysis Parameters Gender Level/Statistics Males Females N= (%) (.) (7.) Age <_ 5(.) (yr) 5 (5.5) (.5) >_ (.7) Mean±SD Median Min Max.9±.... Height Mean±SD.±9. (cm) Median 9. Min Max 5.. Bodyweight Mean±SD 7.±. (kg) Median 5. Min Max 7.. Body surface area (m ) Mean±SD Median Min Max.7±....7 BUN Mean±SD.9±. (mg/dl) Median.9 Min Max.. Serum creatinine Mean±SD.9±.9 (mg/dl) Median. Min Max..5 Diagnosis Bacterialpneumonia Acuteotitismedia Other a) 5(.9) (7.) 7(.) a) a) Viruspneumonia(),Mycoplasmalpneumonia(),Chlamy dialpneumonia() ε ε ε ε ε σ Δ χ Plasma concentration ( g/ml) mg/kg mg/kg Fig.. PlasmaTFLXconcentrationvs.timeprofile. θ θ θ θ θ θ
Table. CovariateselectionoffactorsafectingTFLXpharmacokinetics ModelNo. F- CL/F(L/h)=θ Vd/F(L)=θ Model F- CL/F(L/h)=θ (basemodel) Vd/F(L)=θ CovariancemodelofCL/FandVd/F F-5 CL/F(L/h)=θ (Bodyweight[kg]/5) θ Vd/F(L)=θ F-5 CL/F(L/h)=θ (Bodyweight[kg]/5) θ (finalmodel) Vd/F(L)=θ (Bodyweight[kg]/5) θ OBJ - 9.5-9.5 -.7 -.9 Pvalue <. <. <. a) b) Observed concentration ( g/ml) Predicted concentration ( g/ml) Observed concentration ( g/ml) Individual predicted concentration ( g/ml) Weighted residual ( g/ml) c) 7 5 5 7 Predicted concentration ( g/ml) Weighted residual ( g/ml) 5 d) 7 5 7 9 9 Fig.. Goodness-of-fitplotsforfinalmodel. a)observedvs.predictedconcentration.b)observedvs.individualpredictedconcentration. c)weighted residualvs.predicted concentration.d)weighted residualvs.time after administration. II
Table. FinalTFLXparameterestimateand95%confidenceinterval Parameter Estimatebyoriginaldata Mean±SE 95%CI Bootstrap(N=,) Mean±SD 7.9±.7 θ 7.9±.5 7.. CL/F(L/h)=θ (Bodyweight/5) θ θ.79±.7.5.57.7±.75 θ.±.9. 5..7±. Vd/F(L)=θ (Bodyweight/5) θ θ.±.9.5.7.±. ka(/h).±.7.7..7±.5 Inter-individualvariability CV(%) ω CL/F.±..7.5±. ω Vd/F.±.9..5±.75 ω CL/F,Vd/F.±.5.±. ω ka (r=.9).±.9.7.±.99 Intra-individualvariability σ.7±.5..5±.7 Plasma concentration ( g/ml) kg (n 9) kg (n ) kg (n ) kg (n ) Fig.. Simulatedsteady-stateplasmaTFLXconcentrationafterrepeatedoraladministrationofmg/kgTFLX. Predictedconcentrationswerecalculatedbyusingeachpatient sindividualbayesianparameter.
Table5. PharmacokineticparametersofpediatricpatientsbytheBayesianmethod Agelevel (yr) Dose (mg/kg) Numberof subjects Age (yr) Bodyweight (kg) AUC- (μ g h/ml) Cmax (μ g/ml) <_.±..±..±. 9.9±..±.7.±..±.5.±.5 5 7.5±..±. 5.5±. 5.±. 7.±..±.9.±..55±.5 7.±. 7.±. 5.7±.7.7±..±..5±5..±..9±.9 >_.5±. 9.±.7 7.79±.7.97±. Total 5 57.±.9.5±. 7.5±9. 5.5±5. 7.5±..5±..9±..±.5 Mean±SD Plasma concentration ( g/ml).. mg/kg (predicted) mg/kg (predicted) mg/kg mg/kg MIC 9 ( g/ml). S. pneumoniae. M. (B) catarrhalis, H. influenzae. Fig.. RelationshipbetweenplasmaTFLXconcentrationandMIC9ofcausativeorganisms. Table. ProbabilityofatainingfAUC/MICtargetbyTFLX dosingregimen Probability Dosage MIC(μ g/ml) fauc/mic (mg/kgbid)...5 Eradication S.pneumoniae M.(B.)catarhalis H.influenzae % % 7.% 9.7% / 9/9 / 99.5% %.% 5.5% / / / 7.7% 9.7% BID:twice-dailyadministration Bodyweightfixedat5kg Eradication: Eradication / EradicationandPersistence.%.% / / / S. pneumoniae μ M. (B.) catarrhalis H. influenzae μ μ μ μ μ
Plasma concentration ( g/ml) Adult mg (n, mean SD) Adult mg (n, mean SD) Pedatric mg/kg (predicted) Pedatric mg/kg (predicted) Fig.5. PlasmaTFLXconcentrationvs.adultandpediatrictimeprofile. Predictedconcentrationsofthepediatricpatientswerecalculatedbypopulationmean parameter. Dose mg mg mg mg Formulation Tablet a) Granule Tablet a) Granule Population Table7. Adultvs.pediatricpharmacokineticparameters Adult Adult Adult Adult Numberof subjects 5 Cmax (μ g/ml).5.5±...±.9 AUC- (μ g h/ml).95.±..97 9.±.9 Tmax (h)..±...5±. T/ (h).5.±.5..±. Reference mg/kg b) Granule Pediatric 5.9±. 7.5±..±..±.5 Presentstudy mg Granule Adult.5±..±.9.±.7 5.±. mg/kg b) Granule Pediatric 57.±.5 Themean±SDpharmacokineticparametersundersingledosecondition. a) OZEX R TAB.5(5mgtablet) b) PharmacokineticparametersbytheBayesianmethod.5±..±..±. Presentstudy μ M. (B.) catarrhalis H. influenzae III μ
fauc/mic mg/kg (not exceeding mg/dose) mg/kg (not exceeding mg/dose) 7 5 5 7 Body weight (kg) Fig.. Bodyweightvs.fAUC/MIC calculated bymic.5 μ g/ml. S. pneumoniae μ S. pneumoniae H. influenzae μ μ μ μ S. pneumoniae S. pneumoniae in vitro
Streptococcus pneumoniae Moraxella(Branhamella) catarrhalis Haemophilus influenzae