Levofloxacin 注射剤500 mg 単回投与の健康被験者におけるQT 間隔に対する影響.pdf

=Oqv.3j-FWPGMPYBDJONNHosd)wHgtSZ25t0b?bNi$fGGZgHqZCzlGfggRD!RD!g-FWPGMPYBDJONHosid)w25t0bAbht|Hs0qh0|oU|=|8ghhxS|QUstsOtwgJhH8S|H8tMFWPGMPYBDJOhxgd)hj?$d)8w:#|tGh?$x|?$；t|CUU=h|-Uh25t0oxSJEFSJDJBO25D|#BFUUO25D#S|gBwV:25D125c03333t%:4Ylh；Mo|25wTw!=25c03325D|25c03325DwMFWPGMPYBDJOqqww)25c03325DS|TwvZh5NBYw25DxMFWPGMPYBDJOpNT|pNT|25DxNTTvNTpK|5PSTBEFTEF1PJOUFTVIbUsMqoMc25c03325DNTpKlhQhxqzo|Qhxp25DUGVTlhU|McNTRh*$)4#t,nXZwAL|%x*,S1%S|25bqUh|T|fwwStxNpGVs)UOb(SFQBGMPYBDJOxaSw25wVIbhbU|TQBSGMPYBDJO419tx5E1wmt0o；MvUKM|ZtSMoMFWPGMPYBDJO-79x25wUMqUTthU|tSMo255E1wCUCoM%wQS|1QwHMx|$NBYc033.*$S|6$c033.*$tbwp|sd)XbqLUGVXsqoM|Cw-79NNHwsd)x|7w-79&(tNHwsd)qzoLwS|1QwZqHMU84pVfp|-79NHfOf70-/0-FWPGMPYBDJOw25w；qbMt|25wtSMoItU|bhghI0qMO0ggxUhx|#.*ULHc033NLHc033NwHs0qohQxDhxU*UQwqhwgxhb|%hxOGsNwK|rQw7b|)*7)#T)$7wBZjhx.U*UEQpKlh|Z；U*UEQpKlh|$DSU,jdb|1Q25w7+tCIh&gKMx?Twhxw7UK|H8Dtwgwd)!Zh|25DUNTQ|25UQsMOs?$Uh|)V8ByUNN)HhxNN)Hw|)V8ByUNN)HhxNN)Hw|8ByUNN)HhxNN)Hw|%:U%c033hx%c033w|BBhxB|gd)wN；|h|25w-79qqww)25wTDPOGJEFODFJOUFSWBM$*NTwSp*bhtUApKdXsrg.wg:qh6ABv-79Sbh|d)8ww:#|:#|tBh:#wBx:#U4btlhBv-79Sx|S；=q|ftSMo)1-$OthA?$25|13|234|33S|%:-bh|?-&-*(t|.PSUBSB*OTUSVNFOU|*OD|8JTDPOTJO|64；Moj?$d)8ww:#|thH8wt|wd)t?$bwFqatUJNFNBUDIFECBTFMJOFh25x%:U!=hto!=bL2qsrwTw9t%:wx9s!=Zh|?$xgUitoig|sM6-lhtlh?$wymVXbh|:psxM|swp:wqhg8qSogt0oFw?-；Mh?$x|?$；2VJOUJMFT%BUB1SPDFTTJOH$FOUSF*OEJB1SJWBUF-JNJUFE|.VNCBJ|*OEJBt|N|:S|gUU=|hQU|?$w-S|t_wlhQw?$wALS|xQU|7te+U?$hgpxQ|QS|74we+tv?$-hh|gThbow?$tmMowQU-|tGh?$xt-hQ|j?$|U*S|oH6tb|=Oqv.3Fig.1.Heartratein48healthysubjectsafterasingle60-mininfusionoflevofloxacin()orplacebo(),meanSD.0123484050607080Heartrate(bpm)Timeafterstartofinfusion(h)Table1.Demographicfactorsofsubjects,meanSDTotalFemale,Age65Female,Age45Male,Age65Male,Age45n48n12n12n12n1250.121.769.13.831.26.872.73.527.46.4Age(yr)57.757.5951.545.9355.095.1462.976.5961.386.88Weight(kg)21.952.1022.052.5521.251.9723.021.4421.482.07BMI(kg/m2)102.519.098.916.0115.116.889.717.0106.318.5Ccr(mL/min)Creatinineclearance(Ccr)wascalculatedfrom24-hoururinesamples.Table2.Pharmacokineticparametersobtainedforasingle500mgiv.levofloxacindose,meanSDTotalAge65Age45FemaleMalen48n24n24n24n2410.22.31.91.7Cmax(g/mL)66.314.876.011.556.610.973.512.859.113.2AUC0t(gh/mL)t)Bhw-rs6xrsOtZh5NBYS|$NBYx|6$UxFOtZ|QS|tAh25q%:txwUKh|25xSJEFSJDJBO25D25c03333|#BFUUO25D#25c03333S|gBwV:25D125c03333|gwH8d)tSZ-PH25H!:|-PH33q!:qhsthVqbt%:4YM|AASJEFSJDJBOt4Yqhd)q8NL|g!L|Q!qht|5NBYw25c03325DwTw!=25c03325DS|25c03325Dw-79qqww)25c03325Dw7S|$*wvZh5NBYw25DxQS|tZhx|H8d)wwUJNFNBUDIFECBTFMJOF；Morshh|25Dtoxd)8w:#w:wQSFEPTFCBTFMJOFprshw-rsx44(tWFS44*OTUJUVUF*OD/PSUI$BSPMJOB64；hIIAL0ggxQ|Q|Q|QwgJhdXhxhgxsTlhg5BCMFtb6A$NBYS|6$Ux|QqzoQp|qzopTlh5BCMF5NBYx|:#:#4pKlhA%:)3c03333x|:#Tp-79pxT%c033NFBO4%wcp*|pxT%c033wcp*hJH%:xd)t-79p%c033|p%c033t$tCh%:wTw!=)3x|q5NBYw:#U7GpK|)3x-79p%c033|p%c033pKlhH8d)tSZ%:t0b25c03325Dwx|%:U%c033GVMt#BFUUOpx25Uat4Y|SJEFSJDJBOpx4YqslhJHgB70-/0-FWPGMPYBDJOw25wFig.2.Heartratevs.QT/QTcintervalatbaseline(n48).QTcintervalswerecorrectedusingthreemethods:Fridericiasformula(upperleftpanel),thepopulation(studyspecinullfic)correctionformulaQTcPQT/RR0.410(upperrightpanel),orBazettsformula(lowerleftpanel).300350400450500405060708090QTcF(ms)Heartrate(bpm)300350400450500405060708090Heartrate(bpm)300350400450500405060708090Heartrate(bpm)300350400450500405060708090Heartrate(bpm)QTcP(ms)QTcB(ms)QT(ms)Table3.EffectoflevofloxacinonQT/QTcinterval(ms)95%CIupperlimitMeandifferenceChangefrombaselinenPlaceboLevofloxacin2.148QTcF0.424Male3.824Female2.524Age41.724Age64.648QTcP7.648QTcB8.848QTDifferencebetweenlevofloxacinandplacebotreatmentinchangefrombaselineinQT/QTcin-tervalatTmaxanalyzedusingalinearmixedmodel.Themodelincludestreatment,sequence,andperiodasfixedeffectsandsubjectasarandomeffect.Thetime-matchedbaselineofQTin-terval,age,andgenderareincludedascovariates.QTcPQT/RR0.410.wV:x$*|O:3pK|25D1x25c03333pZhUJNFNBUDIFECBTFMJOFpTbq|5NBYw25Dx-79pNT|pNTpK|25Dw7xNT$*vNTpKlh5BCMF25c03325Dx5NBYpK:#U7GVs!=h25c03325Dx-79qp:#ps)p*|:#xqr)UsTlhJH=Oqv.3Fig.3.QT/QTcintervalin48healthysubjectsafterasingle60-mininfusionoflevofloxacin()orplacebo(),meanSD.QTcPQT/RR0.410.012348360380400420440460QTcF(ms)Timeafterstartofinfusion(h)012348360380400420440460Timeafterstartofinfusion(h)012348360380400420440460Timeafterstartofinfusion(h)012348360380400420440460Timeafterstartofinfusion(h)QTcP(ms)QTcB(ms)QT(ms)Table4.Numberofsubjectsineachcategory,tabulatedbytreatmentChangefrombaselineAbsolutePlaceboLevofloxacinPlaceboLevofloxacinn48n48n48n4830to60ms30to60ms450to480ms450to480ms0000QTcF0000QTcP2201QTcB2176QTNosubjectshowedprolongationofQT/QTc480msor60msfromthebaselineatanytimepoint.QSFEPTFCBTFMJOFpTbq|5NBYw25Dx-79pNT|pNTpK|25Dw7xNT$*vNTpKlhd)t:|25c03325Dw0UNT|NT|NThx|25c03325DUNT|NTQhg:5BCMFtb25c03325DUNTQhg:S|25c03325DUNTQhg:xNpSpK|25c03325DUNTQhghx25c03325DUNTQhgxsTlh6c033A5NBYw25Dq$NBYw$JHtb$NBYUHc033N-wxd)w25D-79wBvSwCx|25DtTstsTlhQwOj25x|-79p70-/0-FWPGMPYBDJOw25wFig.4.ChangefrombaselineinQTcFintervalatTmaxvs.peakplasmaconcentrationoflevofloxacin(range,5.9to15.4g/mL).Male,age45()；female,age45()；male,age65()；andfemale,age65()(n48).SymbolsatCmax0representchangesfrombaselineobservedafterdosingwithplacebo.302010010203005101520ChangefrombaselineinQTcFatTmax(ms)Cmax(g/mL)QMUtE|QUtE|Mc-79qwLxqsTlhQMxd)tCq|gtT&b?$t_wxsX|QMx25tbwpxsTlhQxd)tCq|gQw25xNTpK|?$wGwtthaQwqpKqT|$tOAsqxQsTlhgpx|-79wQtOGsJxsTlhIIIo-79S|wq:#d)t%:wCUh%:wTw!=x|-79UcTtGVTlh%c033S|%c033wHgtSMo-79t%:wsCxNHNHNHwqt；$thU|%:Ct5PbxCoMsMgtSZ-79t%:wC；xX|$sxsMqQ$t|%:UCh|#BFUUOpxa4Y|SJEFSJDJBOp%:CwU|Mc25DUGVtAgpx|25wAtw%:4YMO25D|25D#|25D1；Mhq|%:CpSJEFSJDJBOx4Yqs|25D1U7%:w4YpVhM|gtSZ4Ywx25D#25D125Dqfgw4YwSoMh%:p4Yw25wyVx|%:wCtIhg$sSpKqhgwAx-79NHU5NBYt25Dttbqh25wSq5E1CtxUK|25wUNTpx5E1Cx/POF|NTx6OMJLFMZ|NTx1PTTJCMF|NTx1SPCBCMF|NTxMNPTUEFGJOJUF|NTx%FGJOJUFpKq-79w25DxNT$*vNTpK|5E1CUsMqVospKlhh|-79w25Dw$*vx|*$)&w5IPSPVHI25c03325Dgp25c03325Dw$*vUNTpKyQpKqoMcpKlh25xQsrwQAt!ZQxQ5E1wC:UX25Nw!QUMqUoM|h|5E1w)epK|gpxQhxqzo|Qhxp25DUGVTlhU|McNToMsMqT|gpxEQ0sTlhT|*$)&S|*$)w&YQFSU8PSLJOH(SPVQtU$sA,th?$wMO|Sgh?$；bqp|?$wS-pVOtg-hgxQS|gUpKU|25Dwgj)xNTpK|25wUZbtxGsSpKlhH8d)wwUJNFNBUDIFECBTFMJOFpThqd)QSFEPTFCBTFMJOFpThp|-79w25DS|$*vx|7wALpKlhNT|$*vNTS|NT|$*vNT_x|Dw&*NQMFNFOUBUJPO8PSLJOH(SPVQ2VFTUJPOTOTXFSTtSMo|gU0qsgwxQSFEPTFCBTFMJOFpGpKqMOtbwpK25waSwt$sJx5E1wCpK5E1wCqtxwAUGVX|OsmOswQx|swgALTxc*pVsMT|5E1CbMth6b$BSMTTPOS|Qjsrw5TtSMo|-79tTxoc|hswgpTtslhOt-79w?$w25wxXcTpKlhwp|-79U5E1CbDQxtMq|-79Uh25wxXcTpK|gpTC；sTlhOt|tSMo-79U5E1CbDQxtMqY4VHJZBNB4FOTJUJWFBOESFMJBCMFQSPBSSIZUINJBinvivoBOJNBMNPEFMTGPSQSFEJDUJOHESVHJOEVDFEUPSTBEFTEFQPJOUFTJOQBUJFOUTXJUISFNPEFMMFEIFBSUT#S+1IBSNBDPM*OUFSOBUJPOBM$POGFSFODFPO)BSNPOJBUJPOPG5FDIOJDBM3FRVJSFNFOUTGPS3FHJTUSBUJPOPG1IBSNBDFVUJDBMTGPS)VNBO6TF5IF/PO$MJOJDBM&WBMVBUJPOPG5IF1PUFOUJBMPS%FMBZFE7FOUSJDVMBS3FQPMBSJBUJPO2U*OUFSWBM1SPMPOHBUJPOCZ)VNBO1IBSNBDFVUJDBMT4#(FOFWB4XJUFSMBOEWBJMBCMFBUIUUQc033c033XXXJDIPSHc033-0#c033NFEJBc033.&%*QEG*OUFSOBUJPOBM$POGFSFODFPO)BSNPOJBUJPOPG5FDIOJDBM3FRVJSFNFOUTGPS3FHJTUSBUJPOPG1IBSNBDFVUJDBMTGPS)VNBO6TF5IF$MJOJDBM&WBMVBUJPOPG25c03325D*OUFSWBM1SPMPOHBUJPOBOE1SPBSSIZUINJD1PUFOUJBMGPS/POOUJBSSIZUINJD%SVHT&(FOFWB4XJUFSMBOEWBJMBCMFBUIUUQc033c033XXXJDIPSHc033-0#c033NFEJBc033.&%*QEG#BMM12VJOPMPOFJOEVDFE25JOUFSWBMQSPMPOHBUJPOBOPUTPVOFYQFDUFEDMBTTFGGFDU+OUJNJDSPC$IFNPUIFS3VCJOTUFJO&$BNN+$BSEJPUPYJDJUZPGGMVPSPRVJOPMPOFT+OUJNJDSPC$IFNPUIFSa%w；qow25=Oqv%VQPOU)5JNTJU+4PVXFJOF#(BDIPU#8PMGG.3FHOJFS#5PSTBEFTEFQPJOUFQSPCBCMZSFMBUFEUPTQBSGMPYBDJO&VS+$MJO.JDSPCJPM*OGFDU%JTNH4|GEa|+VOVSVIBNB,5PYJDPMPHZBTTFTTNFOUPGGMVPSPRVJOPMPOFTBDBTFTUVEZIn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w25wOUJNJDSPCHFOUT#MPOEFBV+.；IBP9)BOTFO(%SMJDB,.VUBOUQSFWFOTJPODPODFOUSBUJPOTPGGMVPSPRVJOPMPOFTGPSDMJOJDBMJTPMBUFTPGStreptococuspneumoniae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