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首頁> 美國衛(wèi)生研究院文獻>Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America >A Combination Regimen Design Program Based on Pharmacodynamic Target Setting for Childhood Tuberculosis: Design Rules for the Playground
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A Combination Regimen Design Program Based on Pharmacodynamic Target Setting for Childhood Tuberculosis: Design Rules for the Playground

機譯：基于藥效學(xué)目標(biāo)設(shè)定的兒童結(jié)核病聯(lián)合治療方案設(shè)計方案：操場設(shè)計規(guī)則

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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.
機譯：盡管兒童期和成人結(jié)核病之間的抗生素藥代動力學(xué)，病理學(xué)和微生物負荷存在顯著差異，但仍采用從成年人復(fù)制的藥物治療方案來治療患有結(jié)核病的兒童。我們尋求開發(fā)一種針對不同年齡兒童的新型有效口服治療方案。我們調(diào)查并驗證了與兒童治療失敗和死亡相關(guān)的目標(biāo)藥物濃度不同于成人的目標(biāo)藥物濃度的概念。在此基礎(chǔ)上，我們提出了一個四步計劃，以快速制定針對兒童的治療方案。首先，從單一療法開始，從散布型結(jié)核病的臨床前模型中總結(jié)出最佳藥效的目標(biāo)藥物濃度，該模型概括了兒科藥代動力學(xué)。其次，根據(jù)整個暴露-反應(yīng)表面，檢查了2種藥物組合的協(xié)同作用，拮抗作用和可加性區(qū)域。然后合并與可加性或協(xié)同作用相關(guān)的暴露，并將該方案與標(biāo)準(zhǔn)療法進行比較。第三，增加了第三種藥物的多次暴露，并且與標(biāo)準(zhǔn)療法相比，根據(jù)殺傷斜率確定了3種藥物方案。第四，使用計算機輔助的臨床試驗?zāi)M來確定達到不同年齡組兒童死亡率的臨床劑量。擬議的方案導(dǎo)致了在不到2年的時間內(nèi)，針對成人的兒童從零開始開發(fā)了3種藥物的聯(lián)合治療方案?？梢栽趧游锬Ｐ秃团R床試驗中測試方案和劑量。

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