目的 考察维特克拉(venetoclax)制剂的体外释药行为和在比格犬体内的药动学过程,进行体内体外相关性(IVIVC)的研究。方法 研究测定了维特克拉制剂在不同溶出介质中的溶出曲线;建立维特克拉在比格犬血浆样品中的HPLC测定方法,并对市售的维特克拉片进行饱腹和空腹下比格犬体内的药动学研究;将药物在体外累积溶出度数据与在体内的累积吸收百分数数据进行线性回归,进行IVIVC研究。结果 维特克拉制剂在4种不同溶出介质中体外的释药行为存在明显差异;建立了维特克拉比格犬血样测定方法,该方法简单、准确;维特克拉制剂饱腹和空腹的AUC0→∞分别为(32.38±5.87)和(27.70±6.32)mg·h·L-1,达峰浓度分别为(4.04±0.78)和(3.72±0.69)μg·mL-1,达峰时间分别(6.01±1.04)和(4.27±0.92)h,其中AUC0→∞和达峰时间的差异具有显著性(P＜0.05);体内吸收百分数与在0.2%SDS pH 6.8介质中的体外溶出度有良好的IVIVC。结论 食物可提高维特克拉制剂的生物利用度;本实验筛选出的0.2%SDS pH 6.8介质(桨法,75 r·min-1)可以作为与该制剂体内释药相关的体外溶出条件。
Abstract
OBJECTIVE To investigate the in-vitro release behavior of venetoclax preparations, the pharmacokinetic processes and the correlations between in-vitro release and in-vivo absorption of venetoclax in Beagle dogs. METHODS The dissolution curves of venetoclax preparations in different dissolution media were studied. HPLC method was established for the determination of venetoclax in Beagle dogs, and the pharmacokinetics were studied for commercial venetoclax tablets in Beagle dogs under fed and fasted states.The IVIVC study was carried out by linear regression of cumulative in-vitro drug release and in-vivo absorption accumulation percentage data. RESULTS The in-vitro release behavior among venetoclax formulation in 4 dissolution media were significant difference. The simple, accurate and rapid analysis method for venetoclax blood samples was established. The fed group and the fasted group AUC0→∞ were (32.38±5.87) and (27.70±6.32) mg·h·L-1, the concentration of peak were (4.04±0.78) and (3.72 ±0.69) μg·mL-1, the peak time were (6.01±1.04) and (4.27±0.92) h, respectively, and there was obvious difference (P<0.05) in AUC0→∞ and the peak time between two group. Percentage of in-vivo absorption was in good agreement with in-vitro release in pH 6.8 0.2%SDS media. CONCLUSION The study shows that food could improve the bioavailability of venetoclax formulation; 0.2%SDS pH 6.8 media (paddle, 75 r·min-1) is the in-vivo release of venetoclax associated with the in-vitro release condition.
关键词
维特克拉 /
溶出曲线 /
药动学 /
体内体外相关性
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Key words
venetoclax /
dissolution curve /
pharmacokinetics /
in-vivo in-vitro correlation
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中图分类号：
R944
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参考文献
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脚注
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基金
江苏省“青蓝工程”项目资助(2016);泰州职业技术学院创新型科研团队资助(TZYTD-16-1);2015江苏省大学生创新创业训练计划项目资助(201512106001Y);江苏省卫生计生委科研课题资助(JZ201607);江苏省示范性高职院校建设药学专业师资队伍建设资助(S04-06-03-03)
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