中国药物警戒 ›› 2021, Vol. 18 ›› Issue (7): 606-610.
DOI: 10.19803/j.1672-8629.2021.07.02

• 化学药品一致性评价专栏 • 上一篇    下一篇

盐酸克林霉素棕榈酸酯口服制剂的有效性评价

王晨, 许明哲*   

  1. 中国食品药品检定研究院,北京 102629
  • 收稿日期:2021-01-22 出版日期:2021-07-15 发布日期:2021-07-23
  • 通讯作者: *许明哲,男,博士,抗感染药物质量评价。E-mail：Xumzhe@nifdc.org.cn
  • 作者简介:王晨,男,本科,抗感染药物质量评价。
  • 基金资助:
    重大新药创制国家科技重大专项2017年度（2017zx09101001）

Efficacy of Oral Dosage Forms of Clindamycin Palmitate Hydrochloride

WANG Chen, XU Mingzhe*   

  1. National Institutes for Food and Drug Control, Beijing 102629, China
  • Received:2021-01-22 Online:2021-07-15 Published:2021-07-23

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摘要： 目的 以盐酸克林霉素棕榈酸酯口服制剂为研究对象,探索一种跨剂型跨规格前体类药物口服制剂间的有效性评价策略与方法。方法 测定比格犬口服制剂后的血药浓度数据,建立生理药代动力学模型,采用种属外推和群体化模拟的方法对盐酸克林霉素棕榈酸酯分散片与原研混悬制剂的有效性进行比较。结果 群体化模拟结果显示,供试制剂与参比制剂的血药浓度达峰时间（tmax）结果均为1.9 h,两者的达峰浓度（cmax）均值分别为1.215和1.150 μg/mL,均值比的90%置信区间（CI）为95.6%~115.8%;曲线下面积（AUC0-t）均值分别为5.462和5.331 μg·h/mL,均值比90% CI为88.5%~116.4%。以tmax、cmax和AUC0-t为参数进行生物等效性（BE）预测,供试制剂与参比制剂间各药效参数得到一致结果;进一步对两制剂的抑菌效力进行比较,人体单次口服供试制剂与参比制剂的有效抑菌时间分别为：对革兰阴性菌的血药浓度抑菌时间分别为11.7和11.6 h;对革兰阳性菌的血药浓度抑菌时间分别为9.9和9.7 h,两者无显著性差异。结论 两制剂的有效性水平基本一致。采用该研究思路,利用少量动物体内实测数据对人体BE进行评估预测,相较体外方法,本方法在研究准确性和结果可靠性方面均有较大优势,可作为BE实验预评价过程,在费用低、周期短的基础上,降低BE研究失败风险。

关键词: 盐酸克林霉素棕榈酸酯, 有效性评价, 生理药代动力学模型, 群体化模拟

Abstract: Objective To investigate strategies for efficacy evaluation of oral dosage forms of pro-drugs based on the findings related to oral dosage forms of clindamycin palmitate hydrochloride. Methods Beagles were used to determine the drug concentration in blood. A physiologically based pharmacokinetic (PBPK) model was established and validated with the data collected from animal experiments. The efficacy was compared between clindamycin palmitate hydrochloride dispersible tablets and suspension using inter-species extrapolation and population analog approaches. Results The results showed that the peak time of blood concentration (tmax) was 1.9 hours for both the testing sample and reference sample. The maximum concentration (cmax) was 1.215 and 1.150 μg/mL, respectively, and the 90% confidence interval of the ratio between average values was 95.6%~115.8%.The average value of the area under the curve (AUC0-t) was 5.462 and 5.331 μg·h/mL respectively,and the 90% confidence interval of the ratio between average values was 88.5%~116.4%. The testing sample and reference sample had similar pharmacodynamics parameters and it was predicted that testing sample was bioequivalent to the reference sample based on analysis of tmax, cmax and AUC0-t parameters. There was no significant difference between the testing and reference samples, for the gram-positive bacterium the antimicrobial inhibition time was 11.7 and 11.6 hours respectively, compared to 9.9 and 9.7 hours for the gram-negative bacterium. Conclusion The strategy developed in this research, which used data from only a few animal experiments, has considerable advantages over the in-vitro evaluating methods in terms of accuracy and reliability. It can be used as a low-cost and reliable pre-evaluation tool before conducting the conventional BE study.

Key words: clindamycin palmitate hydrochloride, efficacy evaluation, PBPK model, population analog

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