A phase I, randomized, double-blind, placebo-controlled, ascending single- and multiple-dose study of the pharmacokinetics, safety, and tolerability of oral ceftibuten in healthy adult subjects.

"Elizabeth E. Morgan, Michael N. Dudley, Jeffery S. Loutit, and David C. Griffith are all employees of Qpex Biopharma."

"This project has been funded in whole or in part with Federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under OTA number HHSO100201600026C. J.A. Roberts would like to acknowledge funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP2007007) and an Investigator Grant (APP2009736) as well as an Advancing Queensland Clinical Fellowship."

"This research adhered to the ethical standards outlined in the Declaration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects) and the National Health and Medical Research Council (NHMRC) () (updated 2018) (). The protocol was approved on 5 April 2019 by the Bellberry Human Research Ethics Committee (HREC). The study was registered on ClinicalTrials.gov under the identifier: NCT03939429. 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 cis-ceftibuten (administered form) and trans-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 C max, AUC0–12, and AUC0–INF. Accumulation was calculated as the ratio of AUC0–12 on Days 4 and 10. Adverse events (AEs) were monitored throughout the study. Following single ascending doses, mean cis- and trans-ceftibuten C max were 17.6, 24.1, and 28.1 mg/L, and 1.1, 1.5, and 2.2 mg/L, respectively; cis-ceftibuten urinary recovery accounted for 64.3%–86.9% of the administered dose over 48 h. Following multiple ascending doses, mean cis- and trans-ceftibuten C max were 21.7, 28.1, and 38.8 mg/L, and 1.4, 1.9, and 2.8 mg/L, respectively; cis-ceftibuten urinary recovery accounted for 72.2%–96.4% of the administered dose at steady state. The exposure of cis- and trans-ceftibuten increased proportionally with increasing doses. Cis- and trans-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 cis- and trans-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.)"