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

Abstract

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 (N = 24), subjects received 1 mL rHuPH20 (150 USP units) or placebo (0.9% sodium chloride) SC, followed by 1 or 2 g ceftriaxone (10–350 mg/mL). In Part 2 (N = 30), subjects received 1 g 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 (C_max) and area under plasma concentration–time curve (AUC).

Results:

The highest SC ceftriaxone concentration tested in Part 1 (350 mg/mL) was selected as the Part 2 MTC. In Part 2, median time to maximum concentration (t_max) was 1 hour earlier (P < 0.0001), and C_max was 12% higher (P < 0.0001) for ceftriaxone (350 mg/mL) administered via rHuPH20-facilitated SC versus SC preceded by placebo. IV ceftriaxone led to higher C_max and shorter t_max 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. C_max was higher and t_max 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.

Key words::

• Ceftriaxone
• Cephalosporin
• Intravenous
• Pharmacokinetics
• rHuPH20
• Subcutaneous

Transparency

Declaration of funding

Baxter Healthcare Corporation provided funding for this study.

Declaration of financial/other relationships

All the authors (G.H., F.L., J.B., J.W.T.) are employees of Baxter Healthcare Corporation.

Peer reviewers may receive honoraria from CMRO for their review work. Peer Reviewer 1 and 2 have disclosed that they have no relevant financial interests.

Acknowledgements

The authors wish to thank Halozyme Therapeutics, Inc., San Diego, CA for assistance with trial design and study; Sandra M. Connolly, MD of MDS Pharma Services, Neptune, NJ for conducting the studies; and Barbara J. Goldman, RPh of Advogent, Wayne, NJ for editorial assistance in manuscript preparation (funded by Baxter Healthcare).