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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Biomarker-assisted dose selection for safety and efficacy in early development of PNU-100480 for tuberculosis.
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Biomarker-assisted dose selection for safety and efficacy in early development of PNU-100480 for tuberculosis.

机译：生物标志物辅助剂量选择在PNU-100480结核病早期开发中的安全性和有效性。

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Tuberculosis is a serious global health threat for which new treatments are urgently needed. This study examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the oxazolidinone PNU-100480 in healthy volunteers, using biomarkers for safety and efficacy. Subjects were randomly assigned to PNU-100480 or placebo (4:1) at schedules of 100, 300, or 600 mg twice daily or 1,200 mg daily for 14 days or a schedule of 600 mg twice daily for 28 days to which pyrazinamide was added on days 27 and 28. A sixth cohort was given linezolid at 300 mg daily for 4 days. Signs, symptoms, and routine safety tests were monitored. Bactericidal activity against Mycobacterium tuberculosis was measured in ex vivo whole-blood culture. Plasma drug and metabolite concentrations were compared to the levels required for inhibition of M. tuberculosis growth and 50% inhibition of mitochondrial protein synthesis. All doses were safe and well tolerated. There were no hematologic or other safety signals during 28 days of dosing at 600 mg twice daily. Plasma concentrations of PNU-100480 and metabolites at this dose remained below those required for 50% inhibition of mitochondrial protein synthesis. Cumulative whole-blood bactericidal activity of PNU-100480 at this dose (-0.316 +/- 0.04 log) was superior to the activities of all other doses tested (P < 0.001) and was significantly augmented by pyrazinamide (-0.420 +/- 0.06 log) (P = 0.002). In conclusion, PNU-100480 was safe and well tolerated at all tested doses. Further studies in patients with tuberculosis are warranted. Biomarkers can accelerate early development of new tuberculosis treatments.
机译：结核病是严重的全球健康威胁，因此迫切需要新的治疗方法。这项研究使用生物标志物的安全性和有效性，对健康志愿者中多次递增剂量的恶唑烷酮PNU-100480的安全性，耐受性，药代动力学和药效学进行了研究。将受试者随机分配至PNU-100480或安慰剂（4：1），按每天100、300或600 mg的时间表两次或每天1,200 mg的时间表进行14天，或每天600 mg的时间表连续28天，向其中添加吡嗪酰胺在第27和28天，给第六个队列服用利奈唑胺，每天300 mg，持续4天。监测体征，症状和常规安全性测试。在离体全血培养中测量了对结核分枝杆菌的杀菌活性。将血浆药物和代谢物浓度与抑制结核分枝杆菌生长和抑制线粒体蛋白质合成所需的水平进行比较。所有剂量均安全且耐受性良好。每天两次600毫克服药28天，没有血液学或其他安全性信号。在此剂量下，PNU-100480和代谢物的血浆浓度仍低于抑制线粒体蛋白质合成50％所需的浓度。在此剂量下（-0.316 +/- 0.04 log），PNU-100480的累积全血杀菌活性优于所有其他测试剂量（P <0.001），并且吡嗪酰胺明显增强（-0.420 +/- 0.06）对数）（P = 0.002）。总之，PNU-100480是安全的，并且在所有测试剂量下均具有良好的耐受性。结核病患者有待进一步研究。生物标志物可以加速新的结核病治疗方法的早期开发。

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