Shao Junbo, Liu Xingxing, Lin Jing, Chen Jiao, Xie Xiaoyan
Nanjing Caremo Biomedical Co., Ltd., No. 9 Weidi Road, Nanjing Qixia area, Nanjing, 210033, China.
Jiangsu Dongke Kangde Pharmaceutical Co., Ltd., No. 9 Weidi Road, Nanjing Qixia area, Nanjing, 210033, China.
Drugs R D. 2024 Dec;24(4):517-529. doi: 10.1007/s40268-024-00492-4. Epub 2024 Oct 21.
Azithromycin, a macrolide antibiotic, is commonly used to treat mild-to-moderate bacterial infections. This research aimed to evaluate the pharmacokinetics (PK) properties and bioequivalence (BE) of two azithromycin (EQ 100 mg base/packet) powders for suspension in Chinese healthy participants in fed and fasting conditions.
A total of 90 Chinese healthy participants were enrolled in this nonblinded, single-dose, randomized, semireplicate, three-period, three-sequence, crossover study. Of them, 42 and 40 were categorized to the fed and fasting conditions, respectively. The washout period between doses was 21 days. Blood specimens were harvested prior to administering the drug and 194 h following administration. The plasma levels of azithromycin were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach. PK parameters were measured using noncompartmental analysis. This research compared BE between the reference and test products using the average bioequivalence (ABE) or reference-scaled average bioequivalence (RSABE) method, considering the within-subject variability (S) of the reference preparation. Adverse events (AEs) were monitored to examine safety and tolerability.
The RSABE method (S ≥ 0.294) was used to determine the BE of maximal plasma concentration (C) in both fed and fasting conditions. In the ABE approach, (S < 0.294) was adopted to assess the BE of the area under the plasma concentration-time curve from time zero to the last measurable time point (AUC) and determine the area under the plasma concentration time curve from time zero to time infinity (AUC). In the fasting condition, the point estimate of the test/reference ratio for C was 1.08, with a 95% upper confidence bound of - 0.05 < 0.00. The geometric mean ratio (GMRs) for AUC and AUC was 115.21% [90% confidence interval (CI) 107.25-123.27%] and 113.07% (90% CI 105.14-121.61%), respectively. In the fed condition, the point estimate of the test/reference ratio for C was 0.94, with a 95% upper confidence bound of - 0.10 < 0.00. The GMR for AUC and AUC was 99.51% (90% CI of 91.03-108.78%) and 99.43% (90% CI 91.73-107.78%), respectively. These data all satisfied the BE criteria for drugs with high variability. All AEs were transient and mild, and no severe AEs were observed.
Our study indicated that the test and reference products of azithromycin (EQ 100 mg base/packet) powder for suspension were bioequivalent and safe in healthy Chinese participants, irrespective of the feeding condition. CLINICAL TRIAL REGISTRATION (CHINADRUGTRIALS.ORG.CN): CTR20232646, registered on 25 August 2023.
阿奇霉素是一种大环内酯类抗生素，常用于治疗轻至中度细菌感染。本研究旨在评估两种阿奇霉素（每包含100mg碱基）干混悬剂在中国健康受试者进食和空腹条件下的药代动力学（PK）特性和生物等效性（BE）。
本研究为非盲、单剂量、随机、半重复、三周期、三序列交叉研究，共纳入90名中国健康受试者。其中，42名和40名受试者分别被归类为进食和空腹条件。给药间隔的洗脱期为21天。在给药前和给药后194小时采集血样。采用经过验证的液相色谱-串联质谱（LC-MS/MS）方法分析阿奇霉素的血浆水平。使用非房室分析测量PK参数。本研究采用平均生物等效性（ABE）或参比制剂标化平均生物等效性（RSABE）方法，考虑参比制剂的个体内变异（S），比较参比制剂和受试制剂之间的生物等效性。监测不良事件（AE）以检查安全性和耐受性。
采用RSABE方法（S≥0.294）确定进食和空腹条件下最大血浆浓度（Cmax）的生物等效性。在ABE方法中，采用（S<0.294）评估从0时到最后可测量时间点的血浆浓度-时间曲线下面积（AUC）的生物等效性，并确定从0时到无穷大的血浆浓度时间曲线下面积（AUC∞）。在空腹条件下，Cmax的受试/参比比值的点估计值为1.08，95%置信上限为-0.05<0.00。AUC和AUC∞的几何平均比值（GMR）分别为115.21%[90%置信区间（CI）107.25-123.27%]和113.07%（90%CI 105.14-121.61%）。在进食条件下，Cmax的受试/参比比值的点估计值为0.94，95%置信上限为-0.10<0.00。AUC和AUC∞的GMR分别为99.51%（90%CI 91.03-108.78%）和99.43%（90%CI 91.73-107.78%）。这些数据均符合高变异药物的生物等效性标准。所有AE均为短暂性且轻微，未观察到严重AE。
我们的研究表明，阿奇霉素（每包含100mg碱基）干混悬剂的受试制剂和参比制剂在健康中国受试者中具有生物等效性且安全，无论进食情况如何。临床试验注册（CHINADRUGTRIALS.ORG.CN）：CTR20232646，于2023年8月25日注册。
