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.

Autor: Bradley JS; Department of Pediatrics, University of California San Diego School of Medicine and Rady Children's Hospital of San Diego, San Diego, CA, USA., Makieieva N; Department of Pediatrics, Kharkiv National Medical University, Kharkiv, Ukraine., Tøndel C; Department of Clinical Science, University of Bergen, and Department of Pediatrics, Haukeland University Hospital, Bergen, Norway., Roilides E; Third Department of Pediatrics, Infectious Diseases Unit, School of Medicine, Aristotle University and Hippokration General Hospital, Thessaloniki, Greece., Kelly MS; Department of Pediatrics, Duke University Medical Center, Durham, NC, USA., Patel M; Merck & Co. Inc, Rahway, NJ, USA., Vaddady P; Merck & Co. Inc, Rahway, NJ, USA.; Daiichi Sankyo, Inc., Basking Ridge, NJ, USA., Maniar A; Merck & Co. Inc, Rahway, NJ, USA., Zhang Y; Merck & Co. Inc, Rahway, NJ, USA., Paschke A; Merck & Co. Inc, Rahway, NJ, USA., Chen LF; Merck & Co. Inc, Rahway, NJ, USA.
Jazyk: angličtina
Zdroj: Journal of clinical pharmacology [J Clin Pharmacol] 2023 Dec; Vol. 63 (12), pp. 1387-1397. Date of Electronic Publication: 2023 Sep 02.
DOI: 10.1002/jcph.2334
Abstrakt: Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and 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), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (C max ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean C max and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs 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.
(© 2023 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
Databáze: MEDLINE
Externí odkaz: