Idkaidek Nasir, Arafat Tawfiq, Hamadi Hazim, Hamadi Salim, Al-Adham Ibrahim
Faculty of Pharmacy, Petra University, Amman, Jordan.
Drugs R D. 2017 Mar;17(1):219-224. doi: 10.1007/s40268-016-0170-8.
The aim of this study was to compare human pharmacokinetics and bioequivalence metrics in saliva versus plasma for azithromycin as a model class I drug of the Salivary Excretion Classification System (SECS).
A pilot, open-label, two-way crossover bioequivalence study was done, and involved a single 500-mg oral dose of azithromycin given to eight healthy subjects under fasting conditions, followed by a 3-week washout period. Blood and unstimulated saliva samples were collected over 72 h and deep frozen until analysis by a validated liquid chromatography with mass spectroscopy method. The pharmacokinetic parameters and bioequivalence metrics of azithromycin were calculated by non-compartment analysis using WinNonlin V5.2. Descriptive statistics and dimensional analysis of the pharmacokinetic parameters of azithromycin were performed using Microsoft Excel. PK-Sim V5.6 was used to estimate the effective intestinal permeability of azithromycin.
No statistical differences were shown in area under the concentration curves to 72 h (AUC), maximum measured concentration (C ) and time to maximum concentration (T ) between test and reference azithromycin products (P > 0.05) in the saliva matrix and in the plasma matrix. Due to the high intra-subject variability and low sample size of this pilot study, the 90% confidence intervals of AUC and C did not fall within the acceptance range (80-125%). However, saliva levels were higher than that of plasma, with a longer salivary T . The mean saliva/plasma concentration of test and reference were 2.29 and 2.33, respectively. The mean ± standard deviation ratios of saliva/plasma of AUC, C and T for test were 2.65 ± 1.59, 1.51 ± 0.49 and 1.85 ± 1.4, while for the reference product they were 3.37 ± 2.20, 1.57 ± 0.77 and 2.6 ± 1.27, respectively. A good correlation of R = 0.87 between plasma and saliva concentrations for both test and reference products was also observed. Azithromycin is considered a class I drug based on the SECS, since it has a high permeability and high fraction unbound, and saliva sampling could be used as an alternative to plasma sampling to characterize its pharmacokinetics and bioequivalence in humans when adequate sample size is used.
本研究旨在比较作为唾液排泄分类系统（SECS）中I类药物模型的阿奇霉素在唾液与血浆中的人体药代动力学及生物等效性指标。
开展了一项预试验、开放标签、双向交叉生物等效性研究，对8名健康受试者在禁食条件下口服单剂量500 mg阿奇霉素，随后有3周的洗脱期。在72小时内采集血液和非刺激性唾液样本并深度冷冻，直至采用经过验证的液相色谱 - 质谱法进行分析。阿奇霉素的药代动力学参数和生物等效性指标通过使用WinNonlin V5.2进行非房室分析来计算。使用Microsoft Excel对阿奇霉素的药代动力学参数进行描述性统计和量纲分析。使用PK-Sim V5.6估算阿奇霉素的有效肠道通透性。
在唾液基质和血浆基质中，试验组与参比组阿奇霉素产品在至72小时的浓度曲线下面积（AUC）、最大实测浓度（C）和达峰时间（T）方面均未显示出统计学差异（P>0.05）。由于本预试验研究的受试者内变异性高且样本量小，AUC和C的90%置信区间未落在接受范围内（80 - 125%）。然而，唾液水平高于血浆水平，唾液T更长。试验组和参比组的唾液/血浆平均浓度分别为2.29和2.33。试验组AUC、C和T的唾液/血浆平均±标准差比值分别为2.65±1.59、1.51±0.49和1.85±1.4，而参比产品的相应比值分别为3.37±2.20、1.57±0.77和2.6±1.27。试验组和参比组产品的血浆和唾液浓度之间还观察到良好的相关性，R = 0.87。基于SECS，阿奇霉素被认为是I类药物，因为它具有高通透性和高游离分数，并且当使用足够的样本量时，唾液采样可作为血浆采样的替代方法来表征其在人体中的药代动力学和生物等效性。
