呼吸系統(tǒng)pkpd劉世霆

1、抗菌藥物在呼吸系統(tǒng)的藥代動力學和藥效學,南方醫(yī)院藥學部劉世霆,主要內(nèi)容,抗感染藥物治療的藥代/藥效要求藥物在肺內(nèi)轉(zhuǎn)運和穿透屏障的主要機制藥物在肺內(nèi)轉(zhuǎn)運的影響因素代表性藥物肺內(nèi)的藥代和藥效,抗感染藥物治療的藥代/藥效要求,抗菌藥物的臨床效果除了取決于其抗菌譜、抗菌活性外，還受到它的血漿濃度、到達感染組織的濃度及維持時間的影響?？咕幬镞M入體內(nèi)后必須穿透血-支氣管屏障和血-肺屏障才能到達感染部位。,,抗感染藥物治療的藥代/藥效要求,

2、PK 研究機體對藥物的作用PD 研究藥物對機體的作用,劑量對藥效的影響,藥物對臨床疾病的效果PK/PD 將劑量—時間—濃度—效應的關系聯(lián)系在一起研究,抗感染藥物治療的藥代/藥效要求,,,,,,,,,,,,conc,effect,effect,time,time,conc,PharmacokineticsDose→Conc.vs.time,PK/PDDose→Effect.vs.time,PharmacodynamicsCo

3、nc. →Effect,抗感染藥物治療的藥代/藥效要求,根據(jù)PK/PD參數(shù)的特點按殺菌活性分類第一類：時間依賴殺菌劑 β -內(nèi)酰胺類 (青霉素類、頭孢菌素、氨曲南、碳烯類)，克林和大環(huán)、四環(huán)、萬古霉素在 MIC4-5 倍時,殺菌率即處于飽和殺菌范圍主要依賴于接觸時間血藥濃度超過MIC時間（T>MIC)是與臨床療效相關的主要參數(shù),抗感染藥物治療的藥代/藥效要求,第一類：時間依賴殺菌劑血藥濃度高于 MIC 的時間是

4、最主要參數(shù)給藥間期并不需要都超過MICT>MIC>30-40% 起效T>MIC > 40-50% 保證有效的細菌清除,抗感染藥物治療的藥代/藥效要求,有效的細菌清除：青霉素： T>MIC%>40%頭孢菌素：T>MIC%>50%,肺炎鏈球菌感染動物的模型,頭孢菌素,青霉素,Time above MIC (%),Bacteriologic Cure (%),,,抗感染藥物治療的

5、藥代/藥效要求,抗感染藥物治療的藥代/藥效要求,第二類：濃度依賴殺菌藥物有持續(xù)的后效應氨基糖苷類、喹諾酮類、甲硝唑投藥目標達到最大藥物接觸，藥物濃度越高殺菌率及殺菌范圍也越大24小時AUC/MIC(AUIC)、峰濃度(Cmax)/MIC是療效相關的主要參數(shù),Forrest研究發(fā)現(xiàn)，64例使用喹諾酮類治療的肺炎患者中AUC0-24/MIC＜125時，療效和細菌清除率為42%和26%,當AUC0-24/MIC＞125時，兩者分別為

6、80％和82%，因此認為,AUC0-24/MIC為125時為抗肺炎鏈球菌的最低有效值,抗感染藥物治療的藥代/藥效要求,喹諾酮類屬濃度依賴性抗菌藥,評價療效的主要參數(shù)為Cmax/MIC、AUC/MIC,研究表明左氧氟沙星對革蘭陰性菌24小時AUC/MIC應在100以上,Cmax/MIC達8-10較合適,抗感染藥物治療的藥代/藥效要求,藥物在肺內(nèi)轉(zhuǎn)運和穿透屏障的主要機制,彌散 肺泡-毛細血管膜是雙層的多孔生物膜。 抗菌藥物依賴

7、濃度梯度由血管腔經(jīng)毛細血管孔進入肺間質(zhì)和肺泡上皮村液（epithelial lining fluid,ELF）滲透 藥物穿透非多孔膜的一種方法，通過毛細血管膜細胞轉(zhuǎn)運，亦屬被動過程，但受藥物脂溶性的影響，脂溶性高的藥物易于滲透。主動轉(zhuǎn)運 是一種能量依賴的主動轉(zhuǎn)運機制，在達到飽和狀態(tài)即不再起作用。大環(huán)內(nèi)酯類、克林霉素為巨噬細胞攝取是通過這一過程實現(xiàn)的，而喹諾酮藥物攝取可能部分通過 氨基酸運輸系統(tǒng)。,藥物在

8、肺內(nèi)轉(zhuǎn)運的影響因素,藥物因素：脂溶性、蛋白結(jié)合率解剖因素：肺循環(huán)和支氣管循環(huán)提供巨大的血管床表面積炎癥因素：多數(shù)抗菌藥物在炎癥組織的穿透力提高，但喹諾酮、氯霉素、土霉素、多西環(huán)素、米諾環(huán)素、阿奇霉素則屬非炎癥依耐性。其他 ：呼吸道分泌物的H+、Ca2+、Mg2+等可使氨基糖苷類抗生素滅活。,代表性藥物肺內(nèi)的藥代和藥效,阿奇霉素在肺內(nèi)的藥代和藥效喹諾酮類藥物在肺內(nèi)的藥代和藥效美羅培南在肺內(nèi)的藥代和藥效利奈唑胺在肺內(nèi)的藥代和藥效

9、,阿奇霉素在肺內(nèi)的藥代和藥效,Azithromycin was widely distributed within the lower respiratory tract and sustained levels of the drug were detectable at the last sampling time in lung tissue. Doubling the dose of the antibiotic resulte

10、d in a proportional increase in lung area under the curve (AUC, 1245.4 versus 2514.2 h x mg/kg) and peak tissue concentration (Cmax, 8.93 ± 2.05 versus 18.6 ± 2.20 mg/kg). The pharmacodynamic parameter AUC/MIC

11、for susceptible and intermediate strains of Streptococcus pneumoniae (MICs 0.5 and 2 mg/L, respectively) increased after administration of the 1000 mg schedule compared with 500 mg (AUC/MIC0.5 2414 versus 1144 and AUC/MI

12、C2 2112 versus 814.1 h x mg/kg, respectively) in pulmonary tissue.,Pharmacokinetic parameters of azithromycin in plasma of 48 patients,Each value is the mean ± S.D. of 24 patients. aP < 0.05 compared with azithr

13、omycin 500 mg once daily for 3 days.,Pharmacokinetic and pharmacodynamic parameters of azithromycin in lung and bronchial washing of 48 patients,Cmaxand Tmax are the mean ± S.D. of four patients. aP < 0.05 comp

14、ared with azithromycin 500 mg once daily for 3 days. bPharmacodynamic parameters are calculated on the basis of the MIC for azithromycin-susceptible (0.5 mg/L) or -intermediate (2 mg/L) S. pneumoniae.,喹諾酮類藥物在肺內(nèi)的藥動和藥效,Or

15、al administration of moxifloxacin （ MXF）, 400 mg, levofloxacin （ LEVO）, 500 mg daily for five doses, BAL and venipuncture were completed at 4, 8, 12, or 24 h following the dministration of the last dose.,Steady-State MXF

16、 and LEVO Concentrations in the Plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophage (AM)*,* Values given as mean ± SD, unless otherwise indicated. ? Three subjects. One subject was excluded d

17、ue to insufficient data on the cell differential.,Pharmacodynamic Profile (AUC/MIC) of S pneumoniae for MFX and LEVO in Plasma and ELF*,* MIC90 values of S pneumoniae for each agent were obtained from US surveillance st

18、udies: MXF, 0.25 μg/mL; LEVO, 1 μg/mL.,喹諾酮類藥物在肺內(nèi)的藥動和藥效,The intrapulmonary concentrations of MXF, LEV were superior to those obtained in the plasma. The AM concentrations of all agents studied were more than adequate rel

19、ative to the minimum concentration required to inhibit 90% of the organism population (MIC90) of the common intracellular pathogens (< 1 μg/mL). based on the agent’s current minimum inhibitory concentration profile, w

20、hereas the mean concentrations of MXF and LEVO in the ELF exceed the MIC90 of the S pneumoniae population. Moreover, MXF concentrations exceeded the S pneumoniae susceptibility breakpoint (1.0 μg/mL) at all time points,

21、while 2 of 15 concentrations (13%) failed to maintain LEVO concentrations above the breakpoint (2.0 μg/mL) throughout the dosing interval.,美洛培南在肺內(nèi)的藥代和藥效,Patients received 1 g of meropenem intravenously (i.v.) as a 20-min

22、 infusion every 8 h. In each patient, two microdialysis probes were placed percutaneously under direct vision 2 cm apart well into pneumonic tissue at the end of the operation, directly before the planned fifth dose of

23、meropenem. By use of a microinfusion pump the in situ probes were constantly perfused with Ringer’s solution at a flow rate of 1.5 l/min. Microdialysis was started approximately 30 min after probe insertion, and the pati

24、ents were monitored on the intensive care unit. For calibration, prior to the systemic administration of the study drug, the probes were perfused for 20 min with a solution of the drug, resulting in diffusion from the lu

25、men into the tissue.,美洛培南在肺內(nèi)的藥代和藥效,After a sufficient washout period for the system, meropenem was administered i.v. at a dose of 1 g over 20 min. Sampling of dialysates and venous blood was performed at 20-min intervals

26、 for a period of 8 h. Blood samples were collected in plastic tubes and were immediately centrifuged at 1,600 g for 5 min. Serum and dialysate samples were shock frozen and stored over liquid nitrogen until analysis. Me

27、ropenem was assayed by using high-pressure liquid chromatography method with a limit of detection of 1mg/liter,Pharmacokinetic parameters for meropenem (noncompartmental analysis) in serum, lung interstitial fluid,a Para

28、meters were measured after the i.v. administration of meropenem at 1 g to seven patients with sepsis and undergoing lateral thoracotomy for pneumonia ormetapneumonic pleural empyema. Except for Tmax, results are expres

29、sed as mean and standard deviation.b At the end of the infusion.,美洛培南在肺內(nèi)的藥代和藥效,In the present study, meropenem was administered at a dose of 1 g every 8 h, as recommended by the manufacturer. At this dosage, sufficient

30、concentrations of unbound meropenem were found in the interstitial space fluid of infected lung tissue in patients with metapneumonic empyema. The concentrations of meropenem in tissue were maintained above the MIC90 th

31、reshold for many clinically relevant pathogens, including S. aureus, S. pneumoniae, P. aeruginosa, E. aerogenes, and K. pneumoniae, for up to 6 h (i.e., 80% of the dosing interval).,利奈唑胺多劑口服后的藥代動力學和組織穿透性,利奈唑胺多劑口服后的藥代動力學和

32、組織穿透性,利奈唑胺屬于一類新的抗菌藥——噁唑烷酮類通過抑制蛋白質(zhì)合成的起始階段起抗菌作用在體外和體內(nèi)對革蘭陽性菌具有良好的抗菌作用，包括耐藥菌株目的：評價在600mg多劑口服后，利奈唑胺的藥代動力學和組織穿透性采用水泡液模擬炎癥滲出液,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,材料與方法,受試者：8名，平均年齡29.

33、6±8.7歲，平均體重78.6±7.1 kg，平均身高180.4±14.1 cm，1名受試者因發(fā)熱推出研究，實際參加者7名,受試者7名,,利奈唑胺600㎎/12h,共5劑,給藥前及末次給藥后取血標本,,取標本：給藥前及末次給藥后0.5，1，1.5，2，3，4，6，8，10，和12 h 取血標本，同時取水泡液,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHE

34、MOTHERAPY,2001,45(6),1843-1846,,,,,,,,,,,,,,,,,,,水泡液中藥物濃度檢測,血中藥物濃度檢測,藥代動力學分析,采用HPLC，聯(lián)合三重四極桿質(zhì)譜,采用高效液相色譜（HPLC），每份標本檢測2次，取平均值,標準的無房室，非穩(wěn)態(tài)分析,材料與方法,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,

35、結(jié)果,,,,1例試驗后數(shù)天出現(xiàn)口腔念珠菌病，口服制霉菌素治療,1例在服用首劑利奈唑胺2h后出現(xiàn)心率增快，自88次/分升至120次/分，血壓自150/88mmHg上升至163/90mmHg。該受試者入院觀察不良事件考慮與焦慮有關，但不能除外與研究藥物的關系，因此退出研究,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1

36、846,,圖：末次給藥后血漿和炎癥滲出液中利奈唑胺的濃度,水泡液,血漿,利奈唑胺濃度,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,末次給藥后，利奈唑胺在血漿和炎癥滲出液中的藥代動力學參數(shù),THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843

37、-1846,,,,,,利奈唑胺在水泡液中具有較好的藥動學數(shù)據(jù),6名受試者都產(chǎn)生了水泡，但1名受試者的水泡液的總量不夠用做完整的藥代動力學分析（即至少在清除期要有3個點）,,,,Tmax,Cmax,T1/2,平均比例,利奈唑胺,3h(2h～4h),16.4 mg/ml （ 6.8～36.8 mg/ml）,5.7h,104%（ 80%～130%）,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND

38、CHEMOTHERAPY,2001,45(6),1843-1846,,,,討論,炎癥滲出液中的平均比例為104%，取決于2個因素,12h內(nèi)，利奈唑胺在炎癥滲出液中的平均濃度為4.9 mg/L,多數(shù)金葡菌（甲氧西林敏感及耐藥株）、鏈球菌和腸球菌的MIC≤ 4 μg/ml,提示可用于治療這些細菌所致感染,,,蛋白結(jié)合力：利奈唑胺相對較低，為31%,分布容積：利奈唑胺約為50L,,,THEKLI GEE，et al, ANTIMICROBIA

39、L AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,利奈唑胺與常用PK/PD數(shù)據(jù),氟喹諾酮類和氨基糖苷類的研究表明, AUC24/MIC 反映臨床療效,,,,AUC24/MIC,臨床效果,>100,>125,可能具有較好療效,理想的抗菌作用,利奈唑胺對金葡菌,利奈唑胺對肺炎鏈球菌,215,107.5,研究表明,THEKLI GEE，et al, ANTIMICROBIAL AGENT

40、S AND CHEMOTHERAPY,2001,45(6),1843-1846,利奈唑胺與常用PK/PD數(shù)據(jù),Cmax/MIC的比值，與防止細菌突變發(fā)生耐藥（目前的研究主要來源于氟喹諾酮類和氨基糖苷類的研究，β內(nèi)酰胺類藥物少）有關,,,,Cmax/MIC,出現(xiàn)耐藥的幾率,8～10,低,研究表明,利奈唑胺,9.1,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45

41、(6),1843-1846,利奈唑胺與常用PK/PD數(shù)據(jù),T>MIC小鼠大腿模型的研究顯示，藥物濃度在血漿中的濃度高于細菌MIC的時間與療效有關，其目標值是給藥間隔的40%本研究顯示，利奈唑胺的T>MIC至少為12h超過了每日2次給藥的時間間隔,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,利奈唑胺與常用PK/P

42、D數(shù)據(jù),本研究顯示，血漿和ELF利奈唑胺的T>MIC至少為24h超過了每日2次給藥的時間間隔,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,利奈唑胺在肺組織內(nèi)的藥代動力學,背景,,,,材料與方法,前瞻性、非盲研究,志愿者：25例,,利奈唑胺 600㎎/12h,,,,,,,,給藥5劑后4h,給藥5劑后8h,給藥5劑后12h

43、,給藥5劑后24h,給藥5劑后48h,,血漿和肺組織的穩(wěn)態(tài)濃度,分組,John E. Conte, et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2002, 46(5)1475–1480,材料與方法,支氣管鏡和BAL,采用標準方法，標本離心后，細胞與上清液分別冷凍保存,血標本,給藥前后及完成支氣管鏡、BAL后,標本處理,分離血清，冷凍保存,利奈唑胺分析a.血漿中，利奈唑胺濃度分析：HP

44、LC；b. BAL和細胞懸液中利奈唑胺濃度分析：HPLC聯(lián)合三重四極桿質(zhì)譜；c. ELF體積定量與ELF和AC中利奈唑胺濃度測定：采用尿素法定量后換算濃度,,,,統(tǒng)計,,John E. Conte, et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2002, 46(5)1475–1480,表2. 血漿、ELF和AC中利奈唑胺的濃度,,John E. Conte, et al, ANTIMICR

45、OBIAL AGENTS AND CHEMOTHERAPY, 2002, 46(5)1475–1480,血漿濃度(ug/ml),48小時,24小時,12小時,8小時,4小時,給藥后采樣時間,3.50,4.22,2.38,3.53,4.15,ELF/血漿濃度,0.7±0.8,7.6±6.0,24.3±13.3,31.4±33.0,64.3±33.1,ELF(ug/ml),0.2±

46、;0.2,1.8±0.6,10.2±2.3,8.9±3.2,15.5±4.9,平均濃度,,,,,,,,,,,,,*口服斯沃600mg，每12小時一次， 共給藥5劑,,,,Linezolid concentrations in plasma， pulmonary epithelial lining fluid (ELF), and pulmonary alveolar cells (AC) a,

47、a Data are means ± SD; ranges are given in parentheses.b There were no significant differences among the plasma linezolid concentrations at 12 h after the fourth dose (P ＞0.05).c ELF drug concentrations at 4, 8, 1

48、2, and 24 h were significantly greater than AC drug concentrations at the same times (P ＜0.05).d Concentrations in ELF at 4 h were significantly greater than those at 8, 12, 24, and 48 h (P ＜ 0.05).e n＝4.f BLQ, below

49、level of quantitation.,圖1.行氣管鏡時，血漿內(nèi)的利奈唑胺濃度,金葡菌的MIC90,腸球菌屬的MIC90,肺炎鏈球菌的MIC90,實測濃度,計算濃度,給藥間隔,利奈唑胺濃度,圖2. ELF內(nèi)利奈唑胺濃度,金葡菌的MIC90,腸球菌屬的MIC90,肺炎鏈球菌的MIC90,實測濃度,計算濃度,利奈唑胺濃度,給藥間隔,斯沃在肺上皮細胞襯液中具有較高濃度,Conte JE Jr et al. Antimicrob Agen

50、ts Chemother.2002 ;46 :1475-1480.,斯沃在肺上皮襯液濃度遠高于金黃色葡萄球菌MIC90,一項由25名健康志愿者參加的前瞻性、開放性研究，給予斯沃600mg，po，q12h, 給藥5次后測定受試者血漿及肺上皮襯液中藥物濃度,肺上皮細胞襯液中平均濃度對比（ug/mL）,給藥后時間(小時),,,肺上皮襯液濃度,,,血漿濃度,,,,金葡菌MIC90,4ug/mL,斯沃,萬古霉素,,利奈唑胺組織濃度與血漿濃度的比例

51、,1. Graziani 1988; 2. Matzke 1986; 3. Albanese 2000; 4. Georges 1997; 5. Lamer 1993; 6. Daschner 1987; 7. Blevins 1984; 8. Wilson 2000; 9. Stahl 1987; 10. Wise 1986; 11. Frank 1997; 12. Lovering 2002; 13. SmPC; 14. Gee 2

52、001; 15. Gendjar 2001.,討論,,,,ELF中利奈唑胺的濃度與血漿濃度之比分別,AC中利奈唑胺的濃度與血漿濃度之比分別,4h,8h,16h,24h,48h,4.2±1.4,0.15±0.05,3.1±2.2,2.4±1.2,3.9±2.3,2.3±1.6,0.15±0.14,0.13±0.10,0.11±0.07,未檢出,藥物濃