UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland , Brisbane, Queensland, Australia.
Qpex Biopharma, Inc. , San Diego, California, USA.
Antimicrob Agents Chemother. 2024 Jan 10;68(1):e0109923. doi: 10.1128/aac.01099-23. Epub 2023 Dec 7.
This was a phase I, randomized, double-blind, placebo-controlled, ascending single- and multiple-dose study of oral ceftibuten to describe the pharmacokinetics (PK) of ceftibuten (administered form) and ceftibuten (metabolite), and to describe safety and tolerability at higher than licensed doses. Subjects received single 400, 600, or 800 mg doses of ceftibuten on Days 1 and 4, followed by 7 days of twice-daily dosing from Days 4 to 10. Non-compartmental methods were used to describe parent drug and metabolite PK in plasma and urine. Dose proportionality was examined using , AUC, and AUC. Accumulation was calculated as the ratio of AUC on Days 4 and 10. Adverse events (AEs) were monitored throughout the study. Following single ascending doses, mean - and ceftibuten were 17.6, 24.1, and 28.1 mg/L, and 1.1, 1.5, and 2.2 mg/L, respectively; -ceftibuten urinary recovery accounted for 64.3%-86.9% of the administered dose over 48 h. Following multiple ascending doses, mean - and ceftibuten were 21.7, 28.1, and 38.8 mg/L, and 1.4, 1.9, and 2.8 mg/L, respectively; -ceftibuten urinary recovery accounted for 72.2%-96.4% of the administered dose at steady state. The exposure of and ceftibuten increased proportionally with increasing doses. - and ceftibuten accumulation factor was 1.14-1.19 and 1.28-1.32. The most common gastrointestinal treatment emergent AEs were mild and resolved without intervention. Ceftibuten was well tolerated. Dose proportionality and accumulation of - and -ceftibuten were observed. These results support the ongoing development of ceftibuten at doses up to 800 mg twice-daily. (The study was registered at ClinicalTrials.gov under the identifier NCT03939429.).
这是一项 I 期、随机、双盲、安慰剂对照、递增单剂量和多剂量的口服头孢布烯研究，旨在描述头孢布烯（给药形式）和头孢布烯（代谢物）的药代动力学（PK），并描述高于许可剂量时的安全性和耐受性。受试者在第 1 天和第 4 天接受单次 400、600 或 800 mg 头孢布烯剂量，然后在第 4 天至第 10 天每天两次给药 7 天。非房室方法用于描述血浆和尿液中的母体药物和代谢物 PK。使用 AUC、Cmax 和 AUC 来检查剂量比例性。蓄积作用通过第 4 天和第 10 天的 AUC 比值计算。在整个研究过程中监测不良事件（AE）。单次递增剂量后，平均头孢布烯和头孢布烯分别为 17.6、24.1 和 28.1 mg/L 和 1.1、1.5 和 2.2 mg/L；头孢布烯的尿液回收率在 48 小时内占给药剂量的 64.3%-86.9%。多次递增剂量后，平均头孢布烯和头孢布烯分别为 21.7、28.1 和 38.8 mg/L 和 1.4、1.9 和 2.8 mg/L；头孢布烯的尿液回收率在稳态时占给药剂量的 72.2%-96.4%。和头孢布烯的暴露与剂量成比例增加。和头孢布烯的蓄积因子分别为 1.14-1.19 和 1.28-1.32。最常见的胃肠道治疗相关不良事件为轻度，无需干预即可自行缓解。头孢布烯耐受良好。观察到和头孢布烯的剂量比例性和蓄积作用。这些结果支持头孢布烯在高达 800mg 每日两次的剂量下的进一步开发。（该研究在 ClinicalTrials.gov 上注册，标识符为 NCT03939429.）。
