Pharmacokinetics, safety, and tolerability of imipenem/cilastatin/relebactam in children with confirmed or suspected gram-negative bacterial infections: A Phase 1b, open-label, single-dose clinical trial.

Imipenem/cilastatin/relebactam is approved for treatment of serious gram-negative bacterial infections in adults. This study assessed pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (fixed 2:1 ratio of imipenem/cilastatin to relebactam, with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), the PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%ƒT>MIC) of ≥30% (MIC = 2 μg/mL). For relebactam, the PK/PD target was free area under the concentration-time curve (AUC) normalized to MIC (at 2 μg/mL) ≥8.0 (equivalent to AUC from 0 extrapolated to infinity ≥20.52 μg∙h/mL), respectively. Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges of geometric mean %fT>MIC and maximum concentration (C ) across age cohorts were 56.5%-93.7% and 32.2-38.2 μg/mL, respectively. For relebactam, the ranges of geometric mean C and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 μg/mL and 26.1-55.3 μg·h/mL, respectively. 8/46 (17%) children experienced ≥1 adverse events and 2/46 (4%) children experienced nonserious adverse events that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation. This article is protected by copyright. All rights reserved.