Pharmacological considerations in the design of anti-malarial drug combination therapies - is matching half-lives enough?
Pharmacological considerations in the design of anti-malarial drug combination therapies - is matching half-lives enough?
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DOI：
10.1186/1475-2875-13-62
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发表时间：
2014-02-20
期刊：
影响因子：
3
通讯作者：
Hodel EM
中科院分区：
文献类型：
--
作者：
Hastings IM;Hodel EM
抗疟疾药物现在主要以联合疗法(CT)的形式使用，主要是作为一种防止或减缓耐药性传播的机制。这一策略得到了数学论证的证明，这些论证通常认为耐药性是一种要么全有要么全无的二元遗传特征。在这里，使用药理学而不是纯遗传学的方法来研究耐药性，并认为这为抗疟疾CTs的设计原则提供了更多的洞察力。通常建议CT中成分药物的半衰期相匹配：似乎更重要的是匹配它们在治疗后的抗疟疾活动概况，并确定可以实现这一点的战略。特别是，在人类和寄生虫种群中注意到的药理参数的相当大的差异可能会影响这种匹配，因此，准确地量化药物在CT中的种群药代动力学是至关重要的。增加药物剂量可能会遵循疗效回报递减的规律，即一定剂量的增加并不一定会导致相同百分比的疗效增加。这可能允许在不按比例降低疗效的情况下降低个别药物的剂量，减少任何潜在的毒性，并允许CT中的另一种药物(S)弥补减少的剂量；这是一种危险的策略，将进一步讨论。最后讨论了药物的药代动力学和药效学相互作用以及耐药机制的作用。这一方法为抗疟疾CT产生了理想的目标产品概况(TPP)。抗疟疾药物的供应渠道有限，但在开发阶段了解药理设计原则可以优化CT设计的预部署。这可能有助于防止以前在大多数当前抗疟疾药物部署后发生的药物剂量和/或方案的变化。
Anti-malarial drugs are now mainly deployed as combination therapy (CT), primarily as a mechanism to prevent or slow the spread of resistance. This strategy is justified by mathematical arguments that generally assume that drug ‘resistance’ is a binary all-or-nothing genetic trait. Herein, a pharmacological, rather than a purely genetic, approach is used to investigate resistance and it is argued that this provides additional insight into the design principles of anti-malarial CTs. It is usually suggested that half-lives of constituent drugs in a CT be matched: it appears more important that their post-treatment anti-malarial activity profiles be matched and strategies identified that may achieve this. In particular, the considerable variation in pharmacological parameters noted in both human and parasites populations may compromise this matching and it is, therefore, essential to accurately quantify the population pharmacokinetics of the drugs in the CTs. Increasing drug dosages will likely follow a law of diminishing returns in efficacy, i.e. a certain increase in dose will not necessarily lead to the same percent increase in efficacy. This may allow individual drug dosages to be lowered without proportional decrease in efficacy, reducing any potential toxicity, and allowing the other drug(s) in the CT to compensate for this reduced dosage; this is a dangerous strategy which is discussed further. Finally, pharmacokinetic and pharmacodynamic drug interactions and the role of resistance mechanisms are discussed. This approach generated an idealized target product profile (TPP) for anti-malarial CTs. There is a restricted pipeline of anti-malarial drugs but awareness of pharmacological design principles during the development stages could optimize CT design pre-deployment. This may help prevent changes in drug dosages and/or regimen that have previously occurred post-deployment in most current anti-malarial drugs.
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影响因子：
3
作者：
Ding XC;Ubben D;Wells TN
通讯作者：
Wells TN
DOI：
10.4269/ajtmh.2012.12-0025
发表时间：
2012-08
期刊：
The American journal of tropical medicine and hygiene
影响因子：
--
作者：
Fairhurst RM;Nayyar GML;Breman JG;Hallett R;Vennerstrom JL;Duong S;Ringwald P;Wellems TE;Plowe CV;Dondorp AM
通讯作者：
Dondorp AM
影响因子：
4.9
作者：
Basco, LK;Ringwald, P
通讯作者：
Ringwald, P
影响因子：
56.3
作者：
Amaratunga, Chanaki;Sreng, Sokunthea;Suon, Seila;Phelps, Erika S.;Stepniewska, Kasia;Lim, Pharath;Zhou, Chongjun;Mao, Sivanna;Anderson, Jennifer M.;Lindegardh, Niklas;Jiang, Hongying;Song, Jianping;Su, Xin-zhuan;White, Nicholas J.;Dondorp, Arjen M.;Anderson, Tim J. C.;Fay, Michael P.;Mu, Jianbing;Duong, Socheat;Fairhurst, Rick M.
通讯作者：
Fairhurst, Rick M.
影响因子：
4.9
作者：
Fivelman, QL;Adagu, IS;Warhurst, DC
通讯作者：
Warhurst, DC