《重症患者和抗生素pkpd使用》.ppt

* * 泰阁在上市之初由惠氏公司主导做的替加环素HAP研究，主要与HAP治疗的金标准亚胺培南进行比较。这是一个非劣效性试验，只要结果相当就达到了实验终点和目的 * 研究目的：比较替加环素与亚胺培南治疗HAP的疗效与安全性 实验研究设计方案： 泰阁组：首剂100mg负荷剂量，随后50mg Q12h，若怀疑铜绿：加用头孢他定2g Q8h 亚胺培南-西司他丁组： 500 mg～1g IV q6h*，若怀疑MRSA：加用万古霉素1g Q12h * 临床可评估人群未达到预期试验终点，具体分析可以看到： VAP治愈率：CE人群及mITT人群均未达到非劣性终点 Non-VAP治愈率：CE人群及mITT人群均达到了非劣性终点 那么原因是什么？ * 研究者做了分析发现：在VAP的患者里，泰阁的药物清除明显高于非VAP，数值分别是：VAP=23.3;NO-VAP=20.7，与之相关的也是关系到药物的疗效的因素AUC也发生了较大的影响，VAP时泰阁的AUC为2.726；NO-VAP时AUC为3.198，这也是目前从药物PK/PD看到的呼吸机对于药物的影响的第一个实验，随后在很多药物中也发现了这样的问题，药物剂量越小问题反映越突出。 * Slide # 我们之前了解到泰阁是一个具有时间后效应的时间依赖性抗生素，同时根据研究可以看到替加环素的AUC是剂量的线性关系。因此提高给药剂量，可以提高药物剂量，可以提高AUC，从而提高药物疗效 In an ascending single-dose study by Muralidharan et al, the tigecycline Cmax and AUC increased proportionally to the dose in the range of 12.5 to 300 mg. In fact, a linear relationship was seen between Cmax and dose (r2 = 0.99) and also between AUC and dose (r2 = 0.99). [Muralidharan, 225A and 227H] No significant differences in tigecycline pharmacokinetics were seen between subjects who received tigecycline in the fasting state and those who were given tigecycline in the fed state. [Muralidharan, 225B] Reference Muralidharan G, Micalizzi M, Speth J, et al. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother. 2005a;49:220-229. * 这就是提升剂量的实验研究，在2012年ECCMID公布了这个结果。 * 实验研究共分为3组 泰阁首剂150mg负荷剂量，随后75mgQ12h 泰阁首剂200mg负荷剂量，随后100mgQ12h，这一组是加倍的剂量 泰能1gQ8h 其他的当泰阁组发现铜绿时，头孢他啶覆盖 当泰能组发现MRSA的时候，万古霉素进行覆盖 Global phase 2, multicenter, randomized, double-blind (third-party unblinded) study 210 subjects in 3 cohorts 70% VAP; 30% non-VAP HAP in this trial is defined as pneumonia with onset of symptoms ≥ 48 hours after admission or ≤ 7 days after discharge from hospital (≥ 3 days duration) VAP in this trial is defined as pneumonia with onset of symptoms ≥ 48 hours after endotracheal intubation or ≤ 48 hours after extubation Presence of a new or evolving infiltrate on a chest x-ray film Presence of fever or leukocyto