Safety and pharmacokinetics of subcutaneous ceftriaxone administered with or without recombinant human hyaluronidase (rHuPH20) versus intravenous ceftriaxone administration in adult volunteers

摘要

Objective: To compare pharmacokinetics and safety of recombinant human hyaluronidase (rHuPH20)-facilitated subcutaneous (SC) ceftriaxone administration versus SC ceftriaxone preceded by SC saline placebo or intravenous (IV) ceftriaxone administration. Research design and methods: This Phase I, two-part, placebo-controlled, crossover study was conducted in 54 healthy volunteers. In Part 1 (N24), subjects received 1mL rHuPH20 (150 USP units) or placebo (0.9 sodium chloride) SC, followed by 1 or 2g ceftriaxone (10350mg/mL). In Part 2 (N30), subjects received 1g ceftriaxone at the Part 1 maximum tolerated concentration (MTC) administered either SC preceded by SC rHuPH20 or placebo or IV. Subjects were monitored for adverse events (AEs); blood samples were obtained (Part 2 only) during 48 hours post-dosing for ceftriaxone bioanalysis. Main outcome measures: Part 1 primary endpoint was the SC ceftriaxone (with or without rHuPH20) MTC. Pharmacokinetic parameters were determined in Part 2. Bioequivalence was based on maximum concentration (Cmax) and area under plasma concentrationtime curve (AUC). Results: The highest SC ceftriaxone concentration tested in Part 1 (350mg/mL) was selected as the Part 2 MTC. In Part 2, median time to maximum concentration (tmax) was 1 hour earlier (P0.0001), and Cmax was 12 higher (P0.0001) for ceftriaxone (350mg/mL) administered via rHuPH20-facilitated SC versus SC preceded by placebo. IV ceftriaxone led to higher Cmax and shorter tmax values than either SC treatment. Ceftriaxone exposure (AUC) was comparable among all three treatments. At least 1 AE was experienced by 100 of subjects after SC ceftriaxone and 76 after IV; most commonly reported AEs were infusion-site reactions. Conclusions: Ceftriaxone AUC did not differ significantly between the three administration routes. Cmax was higher and tmax shorter with rHuPH20-facilitated SC than SC preceded by placebo. rHuPH20-facilitated SC ceftriaxone was generally well tolerated. This study is limited by evaluation of healthy adults and absence of repeated-dose groups.