dc.contributor.author | Bradley, John S | |
dc.contributor.author | Makieieva, Nataliia | |
dc.contributor.author | Tøndel, Camilla | |
dc.contributor.author | Roilides, Emmanuel | |
dc.contributor.author | Kelly, Matthew S. | |
dc.contributor.author | Patel, Munjal | |
dc.contributor.author | Vaddady, Pavan | |
dc.contributor.author | Maniar, Alok | |
dc.contributor.author | Zhang, Ying | |
dc.contributor.author | Paschke, Amanda | |
dc.contributor.author | Chen, Luke F | |
dc.date.accessioned | 2024-01-17T09:47:46Z | |
dc.date.available | 2024-01-17T09:47:46Z | |
dc.date.created | 2023-08-11T07:12:27Z | |
dc.date.issued | 2023 | |
dc.identifier.issn | 0091-2700 | |
dc.identifier.uri | https://hdl.handle.net/11250/3112070 | |
dc.description.abstract | 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 (Cmax) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax 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. | en_US |
dc.language.iso | eng | en_US |
dc.publisher | Wiley | en_US |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internasjonal | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/deed.no | * |
dc.title | 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 | en_US |
dc.type | Journal article | en_US |
dc.type | Peer reviewed | en_US |
dc.description.version | publishedVersion | en_US |
dc.rights.holder | Copyright 2023 The Author(s) | en_US |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 1 | |
dc.identifier.doi | 10.1002/jcph.2334 | |
dc.identifier.cristin | 2166276 | |
dc.source.journal | Journal of clinical pharmacology | en_US |
dc.source.pagenumber | 1387-1397 | en_US |
dc.identifier.citation | Journal of clinical pharmacology. 2023, 63 (12), 1387-1397. | en_US |
dc.source.volume | 63 | en_US |
dc.source.issue | 12 | en_US |