药代动力学/药效学参数:优化抗菌药物给药方案

临床应用抗菌药物治疗的目的是清除病原菌,以获得最大疗效并使不良反应降至最低,此外要减少耐药菌的产生。为了达到这个目的,需要正确理解和应用药代动力学(PK)和药效学(PD)原理,设计最佳给药方案。传统上用体外获得的静态数据如最低抑菌浓度(MIC)和最低杀菌浓度(MBC)指导     

抗菌药物药代动力学/药效学与医院肺炎的优化治疗

药代动力学/药效学(pharmacokinetics/pharmacodynamics,PK/PD)是基于抗菌药物体内药动学过程研究其抗菌效果的方法,该理论综合考虑病原体、宿主和药物三者的相互关系,更符合药物抗感染行为与临床实际。PK/PD参数是药代动力学参数和体外抗菌活性参数之间的综合定量参数,包括AUC0-t/MIC、Cmax/MIC和T>MIC等。根据抗菌药物抗菌作用特点可以分为浓度依赖性和时间依赖性抗菌药物,各自用药方式和目标值有所不同。医院肺炎是严重且常见的院内感染,病原种类、细菌耐药性、患者病理状况等有所不同,根据PK/PD原理,设计良好的给药方案,以提高感染治疗成功机率为目标,采用Monte Carlo模拟方法,调整抗菌药物剂量和给药方式,实为优化抗菌治疗最主要的内容之一。     

头孢丙烯临床药代动力学及药效学研究

目的 :研究头孢丙烯药代动力学参数及其与常见致病菌的体外抗菌活性的关系 ,为临床选择合理给药方案提供依据。方法 :用微生物法测定 1 0名健康志愿者中的头孢丙烯血药浓度 ,根据血药浓度 时间曲线求算药代动力学参数 ;以平皿二倍稀释法测定头孢丙烯对常见致病菌的体外抗菌活性。结果 :头孢丙烯 5 0 0mg单次口服给药的体内过程符合二室模型。血药浓度峰值 (cmax)为 (9.36± 1 .1 8)mg/L ,达峰时间 (tmax)为 (1 .2 3± 0 .4 5 )h ,血浆清除半衰期 (t1 /2β)为 (1 .31± 0 .35 )h ,血药浓度 时间曲线下面积 (AUC0 ∞)为 (2 7.0 9± 3.0 6 )h·mg/L ,清除率 (CL)为 (1 8.6 9± 2 .30 )L/h。对社区获得性感染的常见致病菌如肺炎链球菌、酿脓链球菌、流感嗜血杆菌、甲氧西林敏感金黄色葡萄球菌 (MSSA )等的最低抑菌浓度 (MIC)值范围为0 .0 1 6～ 4mg/L ;其中 ,单次口服头孢丙烯 5 0 0mg ,对酿脓链球菌感染可达到T >MIC约 4 0 %以上 ,其他致病菌则小于 30 %。结论 :对确诊为社区获得性呼吸道感染常见的致病菌———酿脓链球菌引起的感染 ,头孢丙烯 5 0 0mg ,每日 1次给药 ,可有较好的疗效 ,但对于肺炎链球菌、流感嗜血杆菌和MSSA等 ,建议增加给药次数或增大单次给药剂量 ,以保证感染的及时控制     

抗真菌药物药代动力学和药效学研究进展

随着侵袭性真菌感染在临床上显著增加,抗真菌药物的研究和开发也是蓬勃发展,特别是近年来两性霉素B脂制剂、三唑类药物、棘白霉素类新药的不断推出,为临床侵袭性真菌感染治疗提供了更多选择。由于侵袭性真菌感染发病情况复杂、临床诊断困难等原因,临床抗真菌治疗存在许多空白与     

抗真菌药物药代动力学和药效学研究进展

随着侵袭性真菌感染在临床上显著增加，抗真菌药物的研究和开发也是蓬勃发展，特别是近年来两性霉素B脂制剂、三唑类药物、棘白霉素类新药的不断推出，为临床侵袭性真菌感染治疗提供了更多选择。由于侵袭性真菌感染发病情况复杂、临床诊断困难等原因，临床抗真菌治疗存在许多空白与疑问，也给真菌感染研究提供了机会。     

抗真菌药物药代动力学和药效学研究进展

随着侵袭性真菌感染在临床上显著增加,抗真菌药物的研究和开发也是蓬勃发展,特别是近年来两性霉素B脂制剂、三唑类药物、棘白霉素类新药的不断推出,为临床侵袭性真菌感染治疗提供了更多选择.     

抗焦虑药布格呋喃的药代动力学和药效学研究

  目的  研究单次和多次服用60或120 mg抗焦虑药布格呋喃的药代动力学及药效学特征。  方法  试验为随机、双盲、安慰剂对照、平行组设计, 在布格呋喃60 mg组和120 mg组分别纳入14名中国健康受试者, 男女各7名。每个剂量组中, 男性和女性受试者随机接受布格呋喃胶囊或安慰剂治疗的比例均为5:2。受试者在研究第1天给药1次, 48 h后, 在研究第3天起每天2次给药, 连续4.5 d。在首次及末次给药后, 分别按照方案规定的时间点连续采集血液和尿液药代动力学样本至给药后48 h, 同时进行躯体摆动、选择反应时间、数字广度、视觉类比量表(visual analogue scale, VAS)等药效学测试。  结果  单次口服60或120 mg布格呋喃后, 其药代动力学参数的平均值分别为:血浆峰浓度C_max(37.7±18.4)和(95.8±34.8)ng/ml, 零至最后一个可定量时间点血浆浓度-时间曲线下面积AUC_0-t为(108±46)和(336±104)h·ng/ml, 表观清除率为(581±203)L/h和(367±122)L/h, 消除相半衰期t_1/2为(10.4±7.1)和(19.8±6.5)h。在每日2次重复给药4.5 d后, 60 mg组和120 mg组布格呋喃的平均C_max分别为(48.5±32.2)和(118.0±20.3)ng/ml, AUC_0-t分别为(241±122)和(656±135)h·ng/ml。除VAS清醒度、VAS外在感受和VAS内在感受外, 本研究检测的绝大多数药效学指标在单次和多次给药后与其他给药组间的差异均无统计学意义(P均 > 0.05)。  结论  每日2次、连续口服布格呋喃约24 h后, 其血浆暴露水平达到稳态, 较单次给药后有2~3倍蓄积。口服60或120 mg布格呋喃在健康受试者中的安全性和耐受性良好。研究选用的药效学指标呈阴性, 可能与药效学方法验证欠充分相关。     

磷霉素及其联合用药的药代动力学/药效学研究进展

<正>磷霉素作为“老”药,具有广谱抗菌活性和良好的药代动力学(pharmacokinetics,PK)特征,在临床抗感染治疗中日益受到重视^[1]。近年来随着对磷霉素研究的深入,发表了大量相关的研究论文,本综述总结了目前磷霉素PK/药效学(pharmacodynamics,PD)数据,重点关注其联合用药的PK/PD研究新进展,为临床合理应用提供参考。1体外PD磷霉素通过与尿苷二磷酸-N-乙酰氨基葡萄糖烯醇式丙酮酸转移酶不可逆地结合,阻止肽聚糖前体N-乙酰胞壁酸合成,从而破坏细胞壁结构导致细菌裂解死亡。     

茯菟丹方的药代动力学研究

目的 建立大鼠血浆中槲皮素浓度的高效液相色谱（HPLC）测定方法,研究菟丝子及茯菟丹方中槲皮素在大鼠体内的药代动力学行为。方法 药代动力学试验设计：取大鼠,按10ml／kg的剂量灌胃给予茯菟丹方灌胃液和菟丝子提取液。分别于预定时间（2、10、15、20、30、45、60、90、120、180、240rain）经眼眶后静脉丛采血,离心分取血浆,处理后进样测定。记录峰面积,计算血药浓度。采用3p97药动学软件进行自动拟合处理。以理论血药浓度值与实验测定值的相关系数最大和赤池信息判据（AIC）最小作为判断标准,选择最佳房室模型．结论 首次建立了血浆中茯菟丹方中槲皮素的RP—HPLC测定方法,阐明了其在大鼠体内的药代动力学特征。     

布洛芬混悬液在正常人体内的相对生物利用度和药代动力学

【目的】比较研究布洛芬混悬液和市售布洛芬片的生物利用度和药代动力学。【方法】选择８ 名健康男性志愿者,随机分为两组,进行单次混悬液或片剂交叉给药６００ ｍ ｇ 后,利用 Ｈ Ｐ Ｌ Ｃ 法测定血浆中布洛芬浓度。【结果】两组血浆的布洛芬浓度分别在（０ ．９２ ±０ ．３３） 和（１ ．６８ ±０ ．５１） ｈ 达到峰值（１３ ．８８ ±１ ．９２） 和（１１ ．０７ ±２ ．５１） μｇ／ｍｌ。血药浓度曲线下面积（ Ａ Ｕ Ｃ） 分别达（４７ ．７７ ±３ ．４６） 和（４５ ．２３ ±５ ．２１） μｇ／（ ｍｉｎ·ｍｌ） ,混悬液的相对生物利用度（ Ｆ） 为（１０５ ．６ ±１１ ．３） ％ 。【结论】布洛芬混悬液和市售布洛芬片两种制剂具有生物等效性。     

Evaluation of clinical dosage of gatifloxacin for respiratory tract infections in elderly patients based on pharmacokinetics/pharmacodynamics (PK/PD)

The efficacy and safety of gatifloxacin (GFLX) was evaluated for elderly patients with respiratory infections. Each patient received one-half (100 mg b.i.d.) or one-quarter (100 mg q.d.) of the conventional dosage of 200 mg b.i.d., after a tentative clinical dosage for GFLX was estimated based on the patient's age and body weight. The subjects were 34 patients aged 65 years or older with mild to moderate acute bronchitis, pneumonia, or chronic respiratory tract infections. The serum concentration of GFLX was measured for each patient, and population and pharmacokinetic (PPK) analysis was performed, using the Bayesian method, to calculate the AUC and maximum drug concentration (Cmax). The overall efficacy rate of GFLX for 33 patients was 87.9% (29/33 patients). GFLX was effective for 75.0% (6/8 patients) in the 100-mg dosage group and 92.0% (23/25 patients) in the 200-mg dosage group. The clinical efficacy was 90.0% (9/10 patients) for acute bronchitis, 86.7% (13/15 patients) for pneumonia, and 87.5% (7/8 patients) for chronic respiratory tract infections. The bacterial eradication rate was 85.7% (12/14 patients). No adverse events or laboratory abnormalities were observed. The AUC values were 11.2-37.5 microg.h/ml and 12.7-111 microg.h/ml for the 100-mg and 200-mg dosage groups, respectively, and the Cmax values were 1.28-3.02 microg/ml and 0.72-6.35 microg/ml, respectively, for the two groups. These results suggest that the dosage of GFLX examined in this study is clinically useful in elderly patients aged 65 or older with acute bronchitis, pneumonia, or chronic respiratory tract infections. The results of PPK analysis with the dosage management also support the efficacy of GFLX.     

Antibacterial activity and PK/PD of ceftriaxone against penicillin-resistant <Emphasis Type="Italic">Streptococcus pneumoniae</Emphasis> and β-lactamase-negative ampicillin-resistant <Emphasis Type="Italic">Haemophilus influenzae</Emphasis> isolates from patients with community-acquired pneumonia

The suitability of ceftriaxone for penicillin-resistant Streptococcus pneumoniae (PRSP) and ampicillin-resistant Haemophilus influenzae (especially β-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae) and the relationship between in vitro antimicrobial activities and pharmacokinetic parameters were evaluated. The values for percentage of time above the MIC (%T>MIC) for ceftriaxone, cefotiam, flomoxef, sulbactam/cefoperazone, sulbactam/ampicillin, and meropenem, using 400 S. pneumoniae isolates and 430 H. influenzae isolates from patients with community-acquired pneumonia (CAP) from more than 100 geographically diverse medical centers during January to July of 2005, were calculated by measuring the MIC for each isolate and by using patameters of pharmacokinetics. A broth microdilution method was used to determine the MIC, using the guidelines of the Clinical and Laboratory Standards Institute (CLSI). Meropenem showed the lowest MIC against penicillin-susceptible S. pneumoniae, followed by sulbactam/cefoperazone and ceftriaxone. Ceftriaxone had the best activity against penicillin-resistant S. pneumoniae and β-lactamase-negative and β-lactamase–producing ampicillin-resistant H. influenzae. Ceftriaxone was unique, showing a long elimination half-life and low MIC values where its serum level duration time was above the MIC for longer than other cephalosporins. Accordingly, the %T>MIC of ceftriaxone for a once-daily administration greatly exceeded the efficacy levels of those for the other antibacterial agents tested. Ceftriaxone has an excellent balance between in vitro antimicrobial activities and pharmacokinetic profiles; and therefore remains effective as a therapeutic agent against PRSP and BLNAR H. influenzae in CAP.     

The effect of pharmacokinetic/pharmacodynamic (PK/PD) parameters of gatifloxacin on its bactericidal activity and resistance selectivity against clinical isolates of Streptococcus pneumoniae

The impact of the pharmacokinetic/pharmacodynamic (PK/PD) parameters (the 24h area under the concentration-time curve [AUC_24h]/minimum inhibitory concentration [MIC] and maximum concentration in serum [C_max]/MIC ratio) after single oral dosing of gatifloxacin on its bactericidal activity and resistance selectivity against quinolone-susceptible clinical isolates of Streptococcus pneumoniae J-69 was investigated using an in vitro PK model. The MICs of gatifloxacin, levofloxacin, and ciprofloxacin were 0.25, 1, and 1µg/ml, respectively. When the range of AUC_24h/MIC ratios was varied from 9.0 to 36 with a constant C_max/MIC ratio of 3.4, the bactericidal activity was correlated with the AUC_24h/MIC ratios. Eradication was observed at an AUC_24h/MIC ratio of 36. On the other hand, the resistance selectivity was associated with the C_max/MIC ratio. Mutant strains were selected at a C_max/MIC ratio of 0.84, but not 1.7 with a constant AUC_24h/MIC ratio of 9.0. These results suggested that an AUC_24h/MIC ratio of 36 and a C_max/MIC ratio of 1.7 might be possible benchmarks to show enough bacterial eradication and prevention of emergence of resistant strains to gatifloxacin, respectively. When the serum concentrations after clinical oral dosing of gatifloxacin (200mg b.i.d.), levofloxacin (100mg t.i.d.), and ciprofloxacin (200mg t.i.d.) were simulated, the bactericidal activity of gatifloxacin was higher than those of levofloxacin and ciprofloxacin. Moreover, no resistant strain was obtained by the exposure to gatifloxacin and levofloxacin, whereas ciprofloxacin selected resistant strains. The clinically relevant oral dosage of gatifloxacin was anticipated to result in a high AUC_24h/MIC₉₀ ratio of 81 and a C_max/MIC₉₀ ratio of 4.4, suggesting that this agent is clinically effective in the treatment of pneumococcal infections.