Pharmacokinetics and Safety of Ceftobiprole in Pediatric Patients

Christopher M Rubino, Mark Polak, Sebastian Schröpf, Hans Georg Münch, Anne Smits, Veerle Cossey, Tomasz Tomasik, Przemko Kwinta, Rima Snariene, Arunas Liubsys, Dace Gardovska, Chi Dang Hornik, Miroslava Bosheva, Christine Ruehle, Karine Litherland, Kamal Hamed, Christopher M Rubino, Mark Polak, Sebastian Schröpf, Hans Georg Münch, Anne Smits, Veerle Cossey, Tomasz Tomasik, Przemko Kwinta, Rima Snariene, Arunas Liubsys, Dace Gardovska, Chi Dang Hornik, Miroslava Bosheva, Christine Ruehle, Karine Litherland, Kamal Hamed

Abstract

Background: Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced-generation, broad-spectrum, intravenous cephalosporin, which is currently approved for the treatment of adults with hospital-acquired or community-acquired pneumonia.

Methods: Noncompartmental pharmacokinetics and safety were analyzed from 2 recently completed pediatric studies, a single-dose, phase 1 study in neonates and infants up to 3 months of age (7.5 mg/kg) and a phase 3 study in patients 3 months to 17 years of age with pneumonia (10-20 mg/kg with a maximum of 500 mg per dose every 8 hours for up to 14 days).

Results: Total ceftobiprole plasma concentrations peaked at the end of infusion. Half life (median ranging from 1.9 to 2.9 hours) and overall exposure (median AUC ranging from 66.6 to 173 μg•h/mL) were similar to those in adults (mean ± SD, 3.3 ± 0.3 hours and 102 ± 11.9 μg•h/mL, respectively). Calculated free-ceftobiprole concentrations in the single-dose study remained above a minimum inhibitory concentration (MIC) of 4 mg/L (fT > MIC of 4 mg/L) for a mean of 5.29 hours after dosing. In the pneumonia study, mean fT > MIC of 4 mg/L was ≥5.28 hours in all dose groups. Ceftobiprole was well tolerated in both studies.

Conclusions: Pharmacokinetic parameters of ceftobiprole characterized in the pediatric population were within the range of those observed in adults. In the pneumonia study, the lowest percentage of the dosing interval with fT > MIC of 4 mg/L was 50.8%, which suggests that pharmacokinetic-pharmacodynamic target attainment can be sufficient in pediatric patients. Ceftobiprole was well tolerated.

Trial registration: ClinicalTrials.gov NCT02527681 NCT03439124.

Conflict of interest statement

C.M.R. is an employee of Institute for Clinical Pharmacodynamics, which received funding for these analyses from Basilea Pharmaceutica International Ltd. A.S.’ research activities are supported by the Clinical Research and Education Council of the University Hospitals Leuven. C.R. and K.L. are employees of, and KH is a consultant for, Basilea Pharmaceutica International Ltd. The other authors have no conflicts of interest to disclose.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

FIGURE 1.
FIGURE 1.
Observed plasma concentration-time profiles for neonates and infants up to 3 months of age (Study BPR-PIP-001, n = 13). h indicates hours; μg, micrograms; mL, milliliters.
FIGURE 2.
FIGURE 2.
Observed ceftobiprole, ceftobiprole medocaril, and open-ring metabolite plasma concentration-time profiles for patients with pneumonia 3 months to 17 years of age (Study BPR-PIP-002). h indicates hours; kg, kilograms; μg, micrograms; mg, milligrams; mL, milliliters.

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Source: PubMed

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