Wu Feng, Zhao Xiuli, Li Xingang, Cui Yimin
Department of Pharmacy, Peking University First Hospital, Beijing, China.
National Institute of Drug Clinical Trial, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Eur J Drug Metab Pharmacokinet. 2019 Jun;44(3):371-378. doi: 10.1007/s13318-018-0522-6.
The disposition of azithromycin in the human eye following topical administration has not been fully explored. Population pharmacokinetic (PopPK) modeling can allow useful conclusions to be drawn based on limited tear sampling data. The aim of this study was therefore to develop and evaluate a PopPK model of azithromycin eyedrops in tears, investigate typical model parameters, and identify potential covariates following single-dose ocular instillation.
A total of 84 tear samples were obtained from 42 healthy volunteers at seven time points over 24 h following topical administration of azithromycin eyedrops (2.5 mL/25 mg). Azithromycin concentrations in the tears were determined using a validated LC-MS/MS assay. PopPK analysis was performed using nonlinear mixed-effects modeling. Intraocular pressure, tear secretion measurement, age, and gender were evaluated as possible covariates. Bootstrap and visual predictive checks were used simultaneously to evaluate the PopPK model. The dosage regimen was further estimated based on Monte Carlo simulation and the area under the curve/minimal inhibitory concentration.
A linear two-compartment first-order elimination model was found to best describe the pharmacokinetic profile of azithromycin in tears. None of the covariates had a significant influence on the typical model parameters. The final PopPK model was demonstrated to be suitable and effective according to bootstrap and visual predictive checks. Twice-daily instillation of azithromycin eyedrops would appear to provide the required antibacterial activity.
A proposed linear two-compartment PopPK model of azithromycin eyedrops was found to be effective at describing the disposition of azithromycin in tears after ocular instillation.
局部给药后阿奇霉素在人眼中的处置情况尚未得到充分研究。群体药代动力学（PopPK）建模能够基于有限的泪液采样数据得出有用的结论。因此，本研究的目的是建立并评估阿奇霉素滴眼液在泪液中的PopPK模型，研究典型的模型参数，并确定单剂量眼内滴注后潜在的协变量。
在局部滴注阿奇霉素滴眼液（2.5 mL/25 mg）后的24小时内，于7个时间点从42名健康志愿者处共采集了84份泪液样本。使用经过验证的液相色谱-串联质谱法（LC-MS/MS）测定泪液中的阿奇霉素浓度。采用非线性混合效应建模进行PopPK分析。将眼压、泪液分泌测量、年龄和性别作为可能的协变量进行评估。同时使用自举法和视觉预测检查来评估PopPK模型。基于蒙特卡洛模拟和曲线下面积/最低抑菌浓度进一步估计给药方案。
发现线性二室一级消除模型最能描述阿奇霉素在泪液中的药代动力学特征。没有一个协变量对典型模型参数有显著影响。根据自举法和视觉预测检查，最终的PopPK模型被证明是合适且有效的。每天两次滴注阿奇霉素滴眼液似乎能提供所需的抗菌活性。
所提出的阿奇霉素滴眼液线性二室PopPK模型被发现能够有效地描述眼内滴注后阿奇霉素在泪液中的处置情况。
