A Combination Regimen Design Program Based on Pharmacodynamic Target Setting for Childhood Tuberculosis: Design Rules for the Playground.
A Combination Regimen Design Program Based on Pharmacodynamic Target Setting for Childhood Tuberculosis: Design Rules for the Playground.
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DOI：
10.1093/cid/ciw472
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发表时间：
2016-11-01
期刊：
影响因子：
--
通讯作者：
Gumbo T
中科院分区：
文献类型：
--
作者：
Srivastava S;Deshpande D;Pasipanodya JG;Thomas T;Swaminathan S;Nuermberger E;Gumbo T
尽管儿童和成人结核病在抗生素药代动力学、病理学和微生物负荷方面存在显著差异，但儿童结核病患者仍采用复制成人的药物方案进行治疗。我们试图开发一种新的和有效的口服治疗方案，具体到不同年龄的儿童。我们调查并验证了与儿童治疗失败和死亡相关的目标药物浓度与成人不同的概念。在此基础上，我们提出了一个快速开发儿童治疗方案的4步计划。首先，最佳疗效的目标药物浓度来自播散性结核的临床前模型，该模型概括了儿科药代动力学，从单药治疗开始。其次，基于整个药物响应表面，检查2种药物组合的协同作用、拮抗作用和加和作用区。然后将与相加或协同作用相关的暴露合并，并将该方案与标准治疗进行比较。第三，增加了第三种药物的几次暴露，并根据与标准治疗相比的杀灭斜率确定了3种药物方案。第四，使用计算机辅助临床试验模拟来确定在不同年龄组的儿童中达到这些致死率的临床剂量。该计划在不到2年的时间内为儿童从头开始开发了3种药物的联合治疗方案，独立于成人治疗方案。可以在动物模型和临床试验中测试方案和剂量。
Children with tuberculosis are treated with drug regimens copied from adults despite significant differences in antibiotic pharmacokinetics, pathology, and the microbial burden between childhood and adult tuberculosis. We sought to develop a new and effective oral treatment regimen specific to children of different ages. We investigated and validated the concept that target drug concentrations associated with therapy failure and death in children are different from those of adults. On that basis, we proposed a 4-step program to rapidly develop treatment regimens for children. First, target drug concentrations for optimal efficacy are derived from preclinical models of disseminated tuberculosis that recapitulate pediatric pharmacokinetics, starting with monotherapy. Second, 2-drug combinations were examined for zones of synergy, antagonism, and additivity based on a whole exposure–response surface. Exposures associated with additivity or synergy were then combined and the regimen was compared to standard therapy. Third, several exposures of the third drug were added, and a 3-drug regimen was identified based on kill slopes in comparison to standard therapy. Fourth, computer-aided clinical trial simulations are used to identify clinical doses that achieve these kill rates in children in different age groups. The proposed program led to the development of a 3-drug combination regimen for children from scratch, independent of adult regimens, in <2 years. The regimens and doses can be tested in animal models and in clinical trials.
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DOI：
10.1093/cid/ciw473
发表时间：
2016-11-01
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Deshpande D;Srivastava S;Nuermberger E;Pasipanodya JG;Swaminathan S;Gumbo T
通讯作者：
Gumbo T
DOI：
10.1093/cid/ciw474
发表时间：
2016-11-01
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Deshpande D;Srivastava S;Nuermberger E;Pasipanodya JG;Swaminathan S;Gumbo T
通讯作者：
Gumbo T
影响因子：
11.8
作者：
Pasipanodya, Jotam G.;Nuermberger, Eric;Gumbo, Tawanda
通讯作者：
Gumbo, Tawanda
影响因子：
6.7
作者：
Momper, J. D.;Mulugeta, Y.;Burckart, G. J.
通讯作者：
Burckart, G. J.
影响因子：
3.7
作者：
METROPOLIS, N;ULAM, S
通讯作者：
ULAM, S