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

Abstract

ABSTRACT 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 , AUC 0–12 , and AUC 0–INF . Accumulation was calculated as the ratio of AUC 0–12 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.)