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首页> 外文期刊>Antimicrobial agents and chemotherapy. >First-Time-in-Human Study and Prediction of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis Treatment
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First-Time-in-Human Study and Prediction of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis Treatment

机译：GSK3036656的首次研究和预测早期杀菌活性，是结核治疗的有效的白云-TRNA合成酶抑制剂

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This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, G5K3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum (C-max) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC(0-tau)) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged G5K3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA(0-14)) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at ClinicalTrials.gov under identifier NCT03075410.)
机译：该第一次（FTIH）研究评估了单一和重复口服剂量的GSK3036656，Leucyl-TRNA合成酶抑制剂的安全性，耐受性，药代动力学和食物效果。在A的A部分中，施用G5K3036656单剂量为5mg（喂食和禁食），15mg和25mg和安慰剂。在B部分中，每天一次施用5和15mg和安慰剂的重复剂量。 GSK3036656表现出在单剂量给药后和给药后的剂量比例增加14天。血清中药物的最大浓度（C-MAX）和浓度 - 时间曲线下的面积从0小时到计量期（AUC（0-TAU））的浓度显示，重复施用约2至3-折叠。药代动力学参数在食物的存在下没有改变。不变的G5K3036656是血浆中唯一检测到的药物相关组分，占尿液中有关药物相关材料的约90％。基于尿液中检测到的总药物相关材料，单个（25mg）和重复（15mg）给药后的最小吸收剂量分别为50％和78％。不变的GSK3036656分别表示25毫克和15mg剂量的至少44％和71％。进行临床试验模拟，以引导FTIH研究期间的剂量升级，并预测在预定的暴露限制期间在预期期II试验中产生最佳早期杀菌活性（EBA（0-14））的GSK3036656剂量范围。在单身和多剂量后，GSK3036656耐受良好，没有报告严重不良事件。 （本研究已在临床节中注册在标识符NCT03075410下。）

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