呼吸系统PKPD-刘世霆

抗菌药物在呼吸系统的药代动力学和药效学南方医院药学部刘世霆主要内容•抗感染药物治疗的药代/药效要求•药物在肺内转运和穿透屏障的主要机制•药物在肺内转运的影响因素•代表性药物肺内的药代和药效抗感染药物治疗的药代/药效要求•抗菌药物的临床效果除了取决于其抗菌谱、抗菌活性外，还受到它的血浆浓度、到达感染组织的浓度及维持时间的影响。抗菌药物进入体内后必须穿透血-支气管屏障和血-肺屏障才能到达感染部位。抗感染药物治疗的药代/药效要求PK研究机体对药物的作用PD研究药物对机体的作用,剂量对药效的影响,药物对临床疾病的效果PK/PD将剂量—时间—浓度—效应的关系联系在一起研究抗感染药物治疗的药代/药效要求conceffecteffecttimetimeconcPharmacokineticsDose→Conc.vs.timePK/PDDose→Effect.vs.timePharmacodynamicsConc.→Effect抗感染药物治疗的药代/药效要求根据PK/PD参数的特点按杀菌活性分类第一类：时间依赖杀菌剂β-内酰胺类(青霉素类、头孢菌素、氨曲南、碳烯类)，克林和大环、四环、万古霉素在MIC4-5倍时,杀菌率即处于饱和杀菌范围主要依赖于接触时间血药浓度超过MIC时间（TMIC)是与临床疗效相关的主要参数抗感染药物治疗的药代/药效要求第一类：时间依赖杀菌剂血药浓度高于MIC的时间是最主要参数给药间期并不需要都超过MICTMIC30-40%起效TMIC40-50%保证有效的细菌清除抗感染药物治疗的药代/药效要求有效的细菌清除：青霉素：TMIC%40%头孢菌素：TMIC%50%肺炎链球菌感染动物的模型Λ头孢菌素o青霉素TimeaboveMIC(%)BacteriologicCure(%)抗感染药物治疗的药代/药效要求抗感染药物治疗的药代/药效要求第二类：浓度依赖杀菌药物有持续的后效应氨基糖苷类、喹诺酮类、甲硝唑投药目标达到最大药物接触，药物浓度越高杀菌率及杀菌范围也越大24小时AUC/MIC(AUIC)、峰浓度(Cmax)/MIC是疗效相关的主要参数Forrest研究发现，64例使用喹诺酮类治疗的肺炎患者中AUC0-24/MIC＜125时，疗效和细菌清除率为42%和26%,当AUC0-24/MIC＞125时，两者分别为80％和82%，因此认为,AUC0-24/MIC为125时为抗肺炎链球菌的最低有效值抗感染药物治疗的药代/药效要求喹诺酮类属浓度依赖性抗菌药,评价疗效的主要参数为Cmax/MIC、AUC/MIC,研究表明左氧氟沙星对革兰阴性菌24小时AUC/MIC应在100以上,Cmax/MIC达8-10较合适抗感染药物治疗的药代/药效要求药物在肺内转运和穿透屏障的主要机制•弥散肺泡-毛细血管膜是双层的多孔生物膜。抗菌药物依赖浓度梯度由血管腔经毛细血管孔进入肺间质和肺泡上皮村液（epithelialliningfluid,ELF）•渗透药物穿透非多孔膜的一种方法，通过毛细血管膜细胞转运，亦属被动过程，但受药物脂溶性的影响，脂溶性高的药物易于渗透。•主动转运是一种能量依赖的主动转运机制，在达到饱和状态即不再起作用。大环内酯类、克林霉素为巨噬细胞摄取是通过这一过程实现的，而喹诺酮药物摄取可能部分通过氨基酸运输系统。药物在肺内转运的影响因素•药物因素：脂溶性、蛋白结合率•解剖因素：肺循环和支气管循环提供巨大的血管床表面积•炎症因素：多数抗菌药物在炎症组织的穿透力提高，但喹诺酮、氯霉素、土霉素、多西环素、米诺环素、阿奇霉素则属非炎症依耐性。•其他：呼吸道分泌物的H+、Ca2+、Mg2+等可使氨基糖苷类抗生素灭活。代表性药物肺内的药代和药效•阿奇霉素在肺内的药代和药效•喹诺酮类药物在肺内的药代和药效•美罗培南在肺内的药代和药效•利奈唑胺在肺内的药代和药效阿奇霉素在肺内的药代和药效•Azithromycinwaswidelydistributedwithinthelowerrespiratorytractandsustainedlevelsofthedrugweredetectableatthelastsamplingtimeinlungtissue.Doublingthedoseoftheantibioticresultedinaproportionalincreaseinlungareaunderthecurve(AUC,1245.4versus2514.2hxmg/kg)andpeaktissueconcentration(Cmax,8.93±2.05versus18.6±2.20mg/kg).ThepharmacodynamicparameterAUC/MICforsusceptibleandintermediatestrainsofStreptococcuspneumoniae(MICs0.5and2mg/L,respectively)increasedafteradministrationofthe1000mgschedulecomparedwith500mg(AUC/MIC0.52414versus1144andAUC/MIC22112versus814.1hxmg/kg,respectively)inpulmonarytissue.Pharmacokineticparametersofazithromycininplasmaof48patientsEachvalueisthemean±S.D.of24patients.aP0.05comparedwithazithromycin500mgoncedailyfor3days.Azithromycin500mgoncedailyfor3daysAzithromycin1000mgoncedailyfor3daysCmax(mg/L)0.18±0.060.32±0.08aTmax(h)1212AUC(h·mg/L)11.62±3.819.83±2.9akel(1/h)0.01803±0.0040.01555±0.003t1/2(h)38.45±6.144.58±6.8CLapp(L/h)43.03±7.250.48±8.7Vapp(L)2386.6±375.33246.7±618.5Pharmacokineticandpharmacodynamicparametersofazithromycininlungandbronchialwashingof48patientsPharmacokineticsAzithromycin500mgoncedailyfor3daysAzithromycin1000mgoncedailyfor3daysbronchialwashinglungbronchialwashinglungCmax(mg/L)0.83±0.078.93±2.051.49±0.09a18.6±2.20aTmax(h)1260126AUC(h·mg/L）70.291245.4139.92514.2AUCbronchialwashing/AUCplasma6.05–7.06–AUClung/AUCplasma–107.2–126.8AUC/MIC0.5(h·mg/L)11.1114441.552414AUC/MIC2(h·mg/L)–814.1–2112TMIC0.5(h)48204102204TMIC2(h)–150–198CmaxandTmaxarethemean±S.D.offourpatients.aP0.05comparedwithazithromycin500mgoncedailyfor3days.bPharmacodynamicparametersarecalculatedonthebasisoftheMICforazithromycin-susceptible(0.5mg/L)or-intermediate(2mg/L)S.pneumoniae.喹诺酮类药物在肺内的药动和药效•Oraladministrationofmoxifloxacin（MXF）,400mg,levofloxacin（LEVO）,500mgdailyforfivedoses,BALandvenipuncturewerecompletedat4,8,12,or24hfollowingthedministrationofthelastdose.Steady-StateMXFandLEVOConcentrationsinthePlasma,pulmonaryepithelialliningfluid(ELF),andalveolarmacrophage(AM)*AgentSampleCollectionTimeAfterLastDose,hSubjects,No.Concentrations,μg/mLPlasmaELFAMMXF443.23±0.8811.66±11.8647.67±47.56842.21±0.597.80±5.08123.25±126.361241.68±0.5310.52±3.6626.21±19.422440.78±0.395.71±6.2832.76±16.48LEVO445.08±2.3115.23±4.5328.50±30.02834.37±.7110.18±6.7426.14±15.731244.60±4.586.85±4.3628.25±12.62441.52±1.422.94±1.748.17±6.10*Valuesgivenasmean±SD,unlessotherwiseindicated.†Threesubjects.Onesubjectwasexcludedduetoinsufficientdataonthecelldifferential.PharmacodynamicProfile(AUC/MIC)ofSpneumoniaeforMFXandLEVOinPlasmaandELF*MatrixAUC/MICRatioMFXLEVOPlasma16687ELF831180*MIC90valuesofSpneumoniaeforeachagentwereobtainedfromUSsurveillancestudies:MXF,0.25μg/mL;LEVO,1μg/mL.喹诺酮类药物在肺内的药动和药效•TheintrapulmonaryconcentrationsofMXF,LEVweresuperiortothoseobtainedintheplasma.TheAMconcentrationsofallagentsstudiedweremorethanadequaterelativetotheminimumconcentrationrequiredtoinhibit90%oftheorganismpopulation(MIC90)ofthecommonintracellularpathogens(1μg/mL).basedontheagent’scurrentminimuminhibitoryconcentrationprofile,whereasthemeanconcentrationsofMXFandLEVOintheELFexceedtheMIC90oftheSpneumoniaepopulation.Moreover,MXFconcentrationsexceededtheSpneumoniaesusceptibilitybreakpoint(1.0μg/mL)atalltimepoints,while2of15concentrations(13%)failedtomaintainLEVOconcentrationsabovethebreakpoint(2.0μg/mL)throughoutthedosinginterval.美洛培南在肺内的药代和药效•Patientsreceived1gofmerope