对于不稳定的产药的血蛋白结合测定:雷姆德西维尔和诺福维尔阿拉芬胺
Anita Wen1, Ann Ran-Ran Qin2, Thomas Tarnowski2
1Department of Clinical Pharmacology, Gilead Sciences, Foster City, CA, USA; Department of Nutrition, University of California, Davis, CA, USA.
确定雷梅西维尔 (RDV) 和诺福维尔阿拉芬胺 (TAF) 的血蛋白结合是至关重要的. 使用平衡透析的新方法,有或没有二沃斯,成功评估了它们的结合,即使是血不稳定.
科学领域:
- 药理动力学 药理动力学
- 药物新陈代谢 药物新陈代谢
- 分析化学 分析化学
背景情况:
- 血蛋白结合 (PPB) 对药物的有效性和安全性至关重要,特别是对于像雷梅西维尔 (RDV) 和特诺福维尔阿拉芬胺 (TAF) 这样的前体药物.
- 人体血中RDV和TAF的不稳定性使PPB的准确确定变得复杂,影响了蛋白质结合改变 (例如,功能障碍,怀孕) 的患者的临床应用.
研究的目的:
- 开发和合格可靠的方法来评估RDV和TAF的血蛋白结合.
- 为了克服前药物在人体血中的不稳定性所带来的挑战,为准确的未结合分数 (fu) 确定.
主要方法:
- 均衡透析 (ED) 用于PPB评估.
- 在ED期间,Dichlorvos用于抑制酶活性并稳定血中的RDV.
- 二沃斯对RDV结合的影响得到了超过的验证.
- 由于其不同的稳定性概况,基于适用性标准,开发了一种单独的ED方法,并对TAF进行了合格.
主要成果:
- 与超过相比,使用二沃斯用于RDV的ED方法对蛋白质结合的影响微不足道.
- TAF的降解速度较慢,而二伏并没有提高其稳定性.
- 在临床研究中,已验证的ED方法已成功应用于PPB的确定.
结论:
- 开发和合格的平衡透析方法使不稳定的前药物RDV和TAF的PPB评估能够准确.
- 使用二沃斯对于稳定RDV是有效的,但不是TAF.
- 这些方法对于了解不同患者群体的药物处置至关重要.
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