Pharmacokinetic-pharmacodynamic analysis of azithromycin extended release in Japanese patients with common respiratory tract infectious disease.
Pharmacokinetic-pharmacodynamic analysis of azithromycin extended release in Japanese patients with common respiratory tract infectious disease.
复制标题
阿奇霉素缓释剂在日本常见呼吸道传染病患者中的药代动力学-药效学分析。
DOI：
10.1093/jac/dkq398
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
T. Suwa
中科院分区：
文献类型：
--
作者：
C. Muto;Ping Liu;K. Chiba;T. Suwa
目标
众所周知，在动物感染模型中，阿奇霉素的疗效与AUC/MIC相关性最好。然而，阿奇霉素的药代动力学-药效学(PK-PD)关系尚未得到临床数据的证实。这项PK-PD分析的目的是描述日本患者阿奇霉素缓释剂(ER)的有效性和安全性的暴露-反应关系，并评估潜在协变量对反应预测的影响。
方法
稀疏的阿奇霉素血药浓度、最低抑菌浓度、有效性和安全性数据来自日本的三个3期研究，即2g单剂量阿奇霉素-ER治疗呼吸道感染。这些稀疏的浓度数据与日本和西方人群中8个阶段1 PK研究的数据相结合，使用非线性混合效应方法开发了一个稳健的人群PK模型。用Logistic回归分析疗效和安全性的暴露-反应关系。
结果
具有一阶吸收和一阶消除且具有滞后时间的两室模型能够很好地描述阿奇霉素-ER的PK，且AUC没有显著的种族差异。AUC/MIC 和 5患者的细菌学和临床成功率(分别为95.8%和100%)明显高于AUC/MIC ≤ 5患者(分别为60.0%和83.3%)。
结论
正如预期的那样，临床和细菌学反应的成功概率与AUC/MIC呈正相关，但与AUC无关。对于暴露-安全关系，与治疗相关的腹泻的发生率与暴露于阿奇霉素呈负相关。
OBJECTIVES
it is known that the efficacy of azithromycin, in animal infection models, is best correlated with AUC/MIC. The pharmacokinetic-pharmacodynamic (PK-PD) relationship for azithromycin, however, has not been previously confirmed with clinical data. The objectives of this PK-PD analysis were to characterize exposure-response relationships for the efficacy and safety of azithromycin extended release (ER) in Japanese patients, and to evaluate the effects of potential covariates on the prediction of response.
METHODS
sparse serum azithromycin concentration, MIC, efficacy and safety data were collected from three Japanese Phase 3 studies of a 2 g single dose of azithromycin-ER for respiratory tract infections. These sparse concentration data were combined with data from eight Phase 1 PK studies in Japanese and Western populations, to develop a robust population PK model using a non-linear mixed effects approach. The exposure-response relationships for efficacy and safety were evaluated using logistic regression.
RESULTS
a two-compartment model with first-order absorption and first-order elimination with a lag time adequately described the PK of azithromycin-ER, without any significant ethnic differences in AUC. The percentage of bacteriological and clinical success in patients with AUC/MIC > 5 (95.8% and 100%, respectively) was much higher than in those with AUC/MIC ≤ 5 (60.0% and 83.3%, respectively).
CONCLUSIONS
as expected, the probabilities of success in the clinical and bacteriological responses were positively associated with AUC/MIC, but not with AUC. For the exposure-safety relationship, the incidence of treatment-related diarrhoea was inversely associated with azithromycin exposure.