OptiMal-PK: an internet-based, user-friendly interface for the mathematical-based design of optimized anti-malarial treatment regimens.
OptiMal-PK: an internet-based, user-friendly interface for the mathematical-based design of optimized anti-malarial treatment regimens.
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DOI：
10.1186/s12936-016-1401-8
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发表时间：
2016-07-07
期刊：
影响因子：
3
通讯作者：
Biagini GA
中科院分区：
文献类型：
--
作者：
Aljayyoussi G;Kay K;Ward SA;Biagini GA
寻找高效的抗疟疾疗法的步伐已经加快，近年来，一些有希望的单一疗法和联合疗法已进入开发的后期阶段。药物开发的一个关键挑战是需要对新药先导的临床效用进行早期评估，因为开发人员往往不清楚是否应该将工作重点放在疗效或代谢稳定性/暴露上，或者实际上不清楚药物化学和生物测试的迭代QSAR(定量结构-活性和关系)循环是否会转化为更好的临床疗效。体外研究提供的基于药代动力学和药效学(PK/PD)的测量可用于此类临床预测。然而，这些预测通常需要定制的数学PK/PD建模专业知识，并且通常在候选开发之后执行，因此，不是在需要做出此类决定的临床前开发阶段。使用Stella®软件开发了一个基于互联网的工具。该工具模拟描述抗疟疾PK/PD关系的多个微分方程式，其中用户可以轻松地输入PK/PD参数。该工具利用一个简单的停车灯系统来指示每种参数组合的有效性。这个工具被称为最佳PK，另外还允许研究药物与已知或定制化合物组合的效果。将从最优PK获得的模拟结果与该工具所基于的先前发布和验证的数学模型进行了比较。该工具还被用来模拟一些现有抗疟疾药物在单一或联合治疗中的PK/PD关系。模拟预测了已发表的这些现有疗法的临床寄生虫学清除活动。最佳PK是由药物化学家和药理学家在临床前抗疟疾药物开发阶段实施的，以探索不同的PK/PD参数对任何新化合物的预测临床活性的影响。它可以帮助研究人员确定一种化合物的哪些药理特征对一种新的化学实体的临床表现最重要，以及伙伴药物如何潜在地提高现有疗法的活性。
The search for highly effective anti-malarial therapies has gathered pace and recent years have seen a number of promising single and combined therapies reach the late stages of development. A key drug development challenge is the need for early assessment of the clinical utility of new drug leads as it is often unclear for developers whether efforts should be focused on efficacy or metabolic stability/exposure or indeed whether the continuation of iterative QSAR (quantitative structure–activity and relationships) cycles of medicinal chemistry and biological testing will translate to improved clinical efficacy. Pharmacokinetic and pharmacodynamic (PK/PD)-based measurements available from in vitro studies can be used for such clinical predictions. However, these predictions often require bespoke mathematical PK/PD modelling expertise and are normally performed after candidate development and, therefore, not during the pre-clinical development phase when such decisions need to be made. An internet-based tool has been developed using STELLA® software. The tool simulates multiple differential equations that describe anti-malarial PK/PD relationships where the user can easily input PK/PD parameters. The tool utilizes a simple stop-light system to indicate the efficacy of each combination of parameters. This tool, called OptiMal-PK, additionally allows for the investigation of the effect of drug combinations with known or custom compounds. The results of simulations obtained from OptiMal-PK were compared to a previously published and validated mathematical model on which this tool is based. The tool has also been used to simulate the PK/PD relationship for a number of existing anti-malarial drugs in single or combined treatment. Simulations were predictive of the published clinical parasitological clearance activities for these existing therapies. OptiMal-PK is designed to be implemented by medicinal chemists and pharmacologists during the pre-clinical anti-malarial drug development phase to explore the impact of different PK/PD parameters upon the predicted clinical activity of any new compound. It can help investigators to identify which pharmacological features of a compound are most important to the clinical performance of a new chemical entity and how partner drugs could potentially improve the activity of existing therapies.