Achieving a quantitative understanding of antiretroviral drug efficacy.
Achieving a quantitative understanding of antiretroviral drug efficacy.
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定量了解抗逆转录病毒药物的功效。
DOI：
10.1086/656688
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发表时间：
2010
期刊：
影响因子：
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通讯作者：
Siliciano,RobertF
中科院分区：
文献类型：
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作者：
Shen,Lin;Siliciano,RobertF
我们写这封信是为了扩展 Henrich 等人最近的一篇文章中提出的一些问题。[1]关于瞬时抑制电位（IIP），这是 Shen 等人开发的一种新的抗病毒活性指标[2, 3]。 IIP 是药物在临床相关浓度下产生的单轮感染事件的对数减少量。由于 IIP 考虑了剂量反应曲线的形状（斜率），因此我们认为，与 IC50 或抑制商（IQ，临床药物浓度与 IC50 之比）等传统药效学指标相比，它更准确地表示了内在抗病毒活性。重要的是，斜率参数包含在所有药理学基本方程中，包括 Hill 方程 [3]、S 形 Emax 模型 [4] 和 Chou Talalay 中值效应方程 [5]。因此，如果不包含该参数，就无法真正理解剂量效应关系。在抗逆转录病毒药物的研究中，它在很大程度上被忽视，直到我们的研究表明，抗逆转录病毒药物的斜率参数变化很大，并且以特定类别的方式变化[2, 3]。事实上，我们发现斜率参数的差异解释了非核苷类逆转录酶抑制剂（NNRTI）和蛋白酶抑制剂（PI）相对于核苷类似物逆转录酶抑制剂（NRTI）具有更高的抗病毒活性。 NNRTI 和 PI 的卓越活性是一个被广泛接受的概念，已纳入 HIV 治疗指南 [6]，但无法通过 IC50 或 IQ 等标准测量来解释。在这方面，整合酶链转移抑制剂（ISTIs）代表了下面讨论的一个特殊情况。Henrich等人[1]研究了药理测量 IIP 和 IQ 与抗逆转录病毒药物临床试验结果之间的关系。毫不奇怪，这两个参数都与治疗 48 周后检测不到 HIV RNA 的患者比例所衡量的结果显示出特别强的相关性。值得注意的是，IIP 的开发是为了预测给定药物浓度下的抗病毒活性，而不是临床结果。正如我们在原始文章 [2, 3] 中指出的那样，除了抗病毒活性之外，临床结果还取决于许多因素，包括药代动力学、分布、毒性、依从性、药物相互作用和耐药障碍。亨里奇等人。表明这些因素在确定药物疗效时占主导地位，并以依非韦伦优于茚地那韦的临床表现为例。有趣的是，这个比较
We are writing to expand upon some issues raised in a recent article by Henrich et al.[1] regarding the Instantaneous Inhibitory Potential (IIP), a novel index of antiviral activity developed by Shen et al.[2, 3]. IIP is the log reduction in single round infection events produced by a drug at clinically relevant concentrations. Because IIP takes into account the shape (slope) of the dose response curve, we have argued that it is a more accurate representation of intrinsic antiviral activity than conventional pharmacodynamic measures such as IC50 or inhibitory quotient (IQ, the ratio of clinical drug concentration to IC50). Importantly, the slope parameter is included in all of the fundamental equations of pharmacology including the Hill equation [3], the sigmoidal Emax model [4], and the Chou Talalay median effect equation [5]. Thus a true understanding of the dose effect relationship cannot be obtained achieved without inclusion of this parameter. It had been largely ignored in studies of antiretroviral drugs until our study showed that the slope parameter varies dramatically and in a class specific way for antiretroviral drugs [2, 3]. Indeed, we showed that differences in the slope parameter explain the higher antiviral activity of the nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) relative to the nucleoside analogue reverse transcriptase inhibitors (NRTIs). The superior activity of the NNRTIs and PIs, a well accepted concept that is incorporated into HIV treatment guidelines [6], is not explained by standard measures like IC50 or IQ. In this regard, the integrase strand transfer inhibitors (ISTIs) represent a special case discussed below.Henrich et al.[1] examined the relationship between the pharmacologic measures IIP and IQ and the outcomes of clinical trials of antiretroviral drugs. Not surprisingly, neither parameter showed a particularly strong correlation with outcome as measured by the fraction of patients who had undetectable HIV RNA after 48 weeks of treatment. It is important to note that IIP was developed to predict antiviral activity at a given drug concentration, not clinical outcome. As we pointed out in our original article [2, 3], clinical outcome is determined by many factors in addition to antiviral activity including pharmacokinetics, distribution, toxicity, adherence, drug interactions, and barriers to resistance. Henrich et al. suggest that these factors dominate the slope in determining drug efficacy and cite the superior clinical performance of efavirenz over indinavir as an example. Interestingly, this comparison