Lutchmun Wandini, Heinrich Norbert, Svensson Elin M, Kloss Florian, Konsten Sarah, Dreisbach Julia, Hoelscher Michael
Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital, Munich, Germany.
German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany.
JAC Antimicrob Resist. 2025 Aug 18;7(4):dlaf127. doi: 10.1093/jacamr/dlaf127. eCollection 2025 Aug.
This first-in-human, single ascending dose study evaluated the safety, tolerability and pharmacokinetics (PK) of the decaprenylphosphoryl-β-D-ribose-2'-epimerase (DprE1) inhibitor BTZ-043.
BTZ-043 was administered as an oral suspension at doses of 125, 250 and 500 mg along with placebo to healthy participants. Safety assessments included evaluation of laboratory parameters, vital signs, physical and neurological examination, and 12-lead ECG. Blood samples for PK assessment in plasma were collected over a 36 h post-dose period. PK parameters were calculated using non-compartmental analysis for parent BTZ-043, metabolites M1 and M2, and BTZ-043 (sum of BTZ-043 and M2) in plasma.
Thirty participants completed the study. All administered BTZ-043 doses were safe and well tolerated. Nervous system disorders (dizziness and headache) and vascular disorders (hypertension and hot flush) were the most frequently reported adverse events (AEs). All AEs were mild or moderate. The parent compound BTZ-043 was rapidly metabolized to metabolite M2 (unknown activity), with median time to maximum concentration in plasma ( ) of 1.5 h (1-2 h). BTZ-043 and M2 had a short half-life. The second main inactive metabolite M1 showed a median of 7-8.5 h and a geometric mean half-life of 8.4-9.0 h. The increases in AUC and maximum concentration of drug in plasma ( ) of BTZ-043 were more than dose-proportional, and those of BTZ-043 were almost dose-proportional. No relevant differences in systemic exposures between males and females were observed.
BTZ-043 was safe, well tolerated and underwent rapid absorption, metabolism and elimination, supporting further clinical development.
这项首次人体单剂量递增研究评估了去甲戊二酰基磷酸化-β-D-核糖-2'-表异构酶（DprE1）抑制剂BTZ-043的安全性、耐受性和药代动力学（PK）。
将BTZ-043制成口服混悬液，以125、250和500毫克的剂量与安慰剂一起给予健康参与者。安全性评估包括实验室参数、生命体征、体格和神经系统检查以及12导联心电图评估。在给药后36小时内采集血浆样本进行PK评估。使用非房室分析法计算血浆中母体BTZ-043、代谢物M1和M2以及BTZ-043（BTZ-043和M2的总和）的PK参数。
30名参与者完成了研究。所有给予的BTZ-043剂量均安全且耐受性良好。神经系统疾病（头晕和头痛）和血管疾病（高血压和潮热）是最常报告的不良事件（AE）。所有AE均为轻度或中度。母体化合物BTZ-043迅速代谢为代谢物M2（活性未知），血浆中达到最大浓度的中位时间（ ）为1.5小时（1 - 2小时）。BTZ-043和M2的半衰期较短。第二种主要的无活性代谢物M1的中位 为7 - 8.5小时，几何平均半衰期为8.4 - 9.0小时。BTZ-043的血浆AUC和药物最大浓度（ ）的增加超过剂量比例，而BTZ-043（BTZ-043和M2的总和）的增加几乎与剂量成比例。未观察到男性和女性在全身暴露方面的相关差异。
BTZ-043安全、耐受性良好，吸收、代谢和消除迅速，支持进一步的临床开发。
