中华传染病杂志
中華傳染病雜誌
중화전염병잡지
CHINESE JOURNAL OF INFECTIOUS DISEASES
2012年
9期
513-519
,共7页
刘晓芳%曹国英%郁继诚%陈渊成%张菁%叶信予%朱德妹%施耀国%张婴元
劉曉芳%曹國英%鬱繼誠%陳淵成%張菁%葉信予%硃德妹%施耀國%張嬰元
류효방%조국영%욱계성%진연성%장정%협신여%주덕매%시요국%장영원
氟喹诺酮类%药代动力学%药效学%高效液相色谱-荧光法%最低抑菌浓度
氟喹諾酮類%藥代動力學%藥效學%高效液相色譜-熒光法%最低抑菌濃度
불규낙동류%약대동역학%약효학%고효액상색보-형광법%최저억균농도
Fluoroquinolones%Pharmacokinetics%Pharmacodynamics%HPLC-fluorometric method%MIC
目的 研究中国健康受试者对吉米沙星的临床药代动力学(PK)和药效学(PD),为优化临床给药方案提供依据.方法 随机、双盲临床试验中,招募20名健康受试者按1∶1比例分为给药组或对照组,分别予以多剂口服320 mg吉米沙星或安慰剂.高效液相色谱荧光法测定受试者血浆和尿液的药物浓度.采用微量稀释法测定吉米沙星对190株社区获得性肺炎常见临床分离菌株的最低抑菌浓度(MIC).以给药后24 h血浆药物浓度时间曲线下面积(AUC0～24h)与MIC的比值(fAUC0～24 h/MIC)和药物峰浓度(Cmax)与MIC的比值(fCmax/MIC)为指标(靶值为25和5),评价吉米沙星的PK和PD特性,并采用蒙特卡洛模拟评价吉米沙星320 mg 1次/d在稳态血药浓度下对上述细菌的累积反应百分比(CFR)及不同MIC水平下的PD达标概率.采用F检验对各组数据作方差齐性检验,采用t检验分析各组间数据.结果 健康受试者多剂口服吉米沙星320 mg 1次/d连续7d给药后的首剂和末剂Cmax分别为(1.55±0.32)和(1.57±0.31) μg/mL,AUC0～24h分别为(7.91±1.52)和(8.91±1.15)h·μg·mL-1,积蓄因子为1.13±0.05.吉米沙星在受试者体内的PK符合二房室模型,分布相和消除相半衰期分别为(0.64±0.17)和(7.10±2.10)h.首剂和末剂给药后24 h平均累积尿排出率分别达34.83％和38.95％.PD研究显示,吉米沙星对肺炎链球菌和卡他莫拉菌的MIC90分别为0.25和0.125 mg/L,对流感嗜血杆菌的MIC90为2 mg/L,而肺炎克雷伯菌和甲氧西林耐药金黄色葡萄球菌对吉米沙星大部分呈现耐药( MIC90＞32 mg/L).当吉米沙星对细菌的MIC值≤0.06mg/L时,吉米沙星320mg 1次/d连续7d给药方案达到fAUC0～24h/MIC和fCmax/MIC的药效学达标概率值均接近100％.结论 中国健康受试者单剂口服吉米沙星320 mg后吸收迅速,多剂给药后第3天达到稳态血药浓度,连续7d给药后有轻度蓄积.PK/PD分析显示,对该药敏感的社区获得性肺炎和慢性阻塞性肺病急性加重者预期可获得良好的临床和细菌学疗效.
目的 研究中國健康受試者對吉米沙星的臨床藥代動力學(PK)和藥效學(PD),為優化臨床給藥方案提供依據.方法 隨機、雙盲臨床試驗中,招募20名健康受試者按1∶1比例分為給藥組或對照組,分彆予以多劑口服320 mg吉米沙星或安慰劑.高效液相色譜熒光法測定受試者血漿和尿液的藥物濃度.採用微量稀釋法測定吉米沙星對190株社區穫得性肺炎常見臨床分離菌株的最低抑菌濃度(MIC).以給藥後24 h血漿藥物濃度時間麯線下麵積(AUC0～24h)與MIC的比值(fAUC0～24 h/MIC)和藥物峰濃度(Cmax)與MIC的比值(fCmax/MIC)為指標(靶值為25和5),評價吉米沙星的PK和PD特性,併採用矇特卡洛模擬評價吉米沙星320 mg 1次/d在穩態血藥濃度下對上述細菌的纍積反應百分比(CFR)及不同MIC水平下的PD達標概率.採用F檢驗對各組數據作方差齊性檢驗,採用t檢驗分析各組間數據.結果 健康受試者多劑口服吉米沙星320 mg 1次/d連續7d給藥後的首劑和末劑Cmax分彆為(1.55±0.32)和(1.57±0.31) μg/mL,AUC0～24h分彆為(7.91±1.52)和(8.91±1.15)h·μg·mL-1,積蓄因子為1.13±0.05.吉米沙星在受試者體內的PK符閤二房室模型,分佈相和消除相半衰期分彆為(0.64±0.17)和(7.10±2.10)h.首劑和末劑給藥後24 h平均纍積尿排齣率分彆達34.83％和38.95％.PD研究顯示,吉米沙星對肺炎鏈毬菌和卡他莫拉菌的MIC90分彆為0.25和0.125 mg/L,對流感嗜血桿菌的MIC90為2 mg/L,而肺炎剋雷伯菌和甲氧西林耐藥金黃色葡萄毬菌對吉米沙星大部分呈現耐藥( MIC90＞32 mg/L).噹吉米沙星對細菌的MIC值≤0.06mg/L時,吉米沙星320mg 1次/d連續7d給藥方案達到fAUC0～24h/MIC和fCmax/MIC的藥效學達標概率值均接近100％.結論 中國健康受試者單劑口服吉米沙星320 mg後吸收迅速,多劑給藥後第3天達到穩態血藥濃度,連續7d給藥後有輕度蓄積.PK/PD分析顯示,對該藥敏感的社區穫得性肺炎和慢性阻塞性肺病急性加重者預期可穫得良好的臨床和細菌學療效.
목적 연구중국건강수시자대길미사성적림상약대동역학(PK)화약효학(PD),위우화림상급약방안제공의거.방법 수궤、쌍맹림상시험중,초모20명건강수시자안1∶1비례분위급약조혹대조조,분별여이다제구복320 mg길미사성혹안위제.고효액상색보형광법측정수시자혈장화뇨액적약물농도.채용미량희석법측정길미사성대190주사구획득성폐염상견림상분리균주적최저억균농도(MIC).이급약후24 h혈장약물농도시간곡선하면적(AUC0～24h)여MIC적비치(fAUC0～24 h/MIC)화약물봉농도(Cmax)여MIC적비치(fCmax/MIC)위지표(파치위25화5),평개길미사성적PK화PD특성,병채용몽특잡락모의평개길미사성320 mg 1차/d재은태혈약농도하대상술세균적루적반응백분비(CFR)급불동MIC수평하적PD체표개솔.채용F검험대각조수거작방차제성검험,채용t검험분석각조간수거.결과 건강수시자다제구복길미사성320 mg 1차/d련속7d급약후적수제화말제Cmax분별위(1.55±0.32)화(1.57±0.31) μg/mL,AUC0～24h분별위(7.91±1.52)화(8.91±1.15)h·μg·mL-1,적축인자위1.13±0.05.길미사성재수시자체내적PK부합이방실모형,분포상화소제상반쇠기분별위(0.64±0.17)화(7.10±2.10)h.수제화말제급약후24 h평균루적뇨배출솔분별체34.83％화38.95％.PD연구현시,길미사성대폐염련구균화잡타막랍균적MIC90분별위0.25화0.125 mg/L,대류감기혈간균적MIC90위2 mg/L,이폐염극뢰백균화갑양서림내약금황색포도구균대길미사성대부분정현내약( MIC90＞32 mg/L).당길미사성대세균적MIC치≤0.06mg/L시,길미사성320mg 1차/d련속7d급약방안체도fAUC0～24h/MIC화fCmax/MIC적약효학체표개솔치균접근100％.결론 중국건강수시자단제구복길미사성320 mg후흡수신속,다제급약후제3천체도은태혈약농도,련속7d급약후유경도축적.PK/PD분석현시,대해약민감적사구획득성폐염화만성조새성폐병급성가중자예기가획득량호적림상화세균학료효.
Objective To investigate the clinical pharmacokinetics (PK) and pharmacodynamics (PD) of gemifloxacin tablet in healthy Chinese volunteers and to provide evidences for optimal clinical dosing.Methods Twenty volunteers were enrolled in the randomized (1∶1) double-blind study,and divided into administration group and control group.Each group received multiple oral doses of 320 mg of gemifloxacin tablet or placebo.The plasma and urine samples for gemifloxacin were analyzed by igh-performance liquid chromatogram (HPLC)-fluorometric method. The minimum inhibition concentrations (MIC) of gemifloxacin against 190 clinical isolates were determined by broth microdilution method.The fAUC0～24 h/MIC and fCmax/MIC,with target value of 25 and 5,were used as the indices to evaluate PK and PD characteristics of gemifloxacin. The cumulative fraction of response (CFR) of gemifloxacin against each bacterium and the probability of target attainment (PTA) under various MIC level were evaluated using Monte Carlo simulation following multiple administration at steady state.Results The Cmax of gemifloxacin after once-daily oral doses for 7 days were (1.55 ±0.32) μg/mL and (1.57±0.31) μg/mL for the first and last dose,while the AUC0～24 h were (7.91±1.52) and (8.91±1.15) h · μg · mL-1,respectively.The accumulation factor was 1.13±0.05.The time-profile of gemifloxacin could be described using two-compartment model and the half-life of distribution and elimination phase were (0.64 ± 0.17) and (7.10 ± 2.10) h,respectively. The cumulative urinary excretion rates within 24 h of gemifloxacin were 34.83 ％ and 38.95 ％ for the first and the last dose,respectively.PD study showed that the MIC90 of gemifloxacin were 0.25 mg/L and 0.125 mg/L against Streptococcus pneumoniae and Moraxelle catarrhalis,respectively,while the MIC90 was 2 mg/L against Hemophilus influenza. However,most of Klebsiella pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) were resistant to gemifloxacin ( MIC90 ＞ 32mg/L).The PTA values of fAUC0～24 h/MIC and fCmax/MIC of gemifloxacin 320 mg daily for 7 days were close to 100％ when MIC was ≤0.06 mg/L.Conclusions Gemifloxacin is rapidly absorbed after oral administration of single doses in healthy Chinese volunteers,and the plasma concentration could reach steady state at the third day,while a minimal accumulation is shown after consecutive 7 days dosing.The PK/PD analysis suggests that the favorable clinical and bacteriological efficacy could be obtained when using this regimen in treatment of sensitive patients with community-acquired pneumonia and acute exacerbation of chronic obstructive pulmonary disease.
