PMID- 37562063
OWN - NLM
STAT- MEDLINE
DCOM- 20231110
LR  - 20231121
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Linking)
VI  - 63
IP  - 12
DP  - 2023 Dec
TI  - 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.
PG  - 1387-1397
LID - 10.1002/jcph.2334 [doi]
AB  - 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.
CI  - (c) 2023 The Authors. The Journal of Clinical Pharmacology published by Wiley 
      Periodicals LLC on behalf of American College of Clinical Pharmacology.
FAU - Bradley, John S
AU  - Bradley JS
AD  - Department of Pediatrics, University of California San Diego School of Medicine 
      and Rady Children's Hospital of San Diego, San Diego, CA, USA.
FAU - Makieieva, Nataliia
AU  - Makieieva N
AD  - Department of Pediatrics, Kharkiv National Medical University, Kharkiv, Ukraine.
FAU - Tondel, Camilla
AU  - Tondel C
AD  - Department of Clinical Science, University of Bergen, and Department of 
      Pediatrics, Haukeland University Hospital, Bergen, Norway.
FAU - Roilides, Emmanuel
AU  - Roilides E
AD  - Third Department of Pediatrics, Infectious Diseases Unit, School of Medicine, 
      Aristotle University and Hippokration General Hospital, Thessaloniki, Greece.
FAU - Kelly, Matthew S
AU  - Kelly MS
AD  - Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
FAU - Patel, Munjal
AU  - Patel M
AUID- ORCID: 0000-0001-6892-0899
AD  - Merck & Co. Inc, Rahway, NJ, USA.
FAU - Vaddady, Pavan
AU  - Vaddady P
AD  - Merck & Co. Inc, Rahway, NJ, USA.
AD  - Daiichi Sankyo, Inc., Basking Ridge, NJ, USA.
FAU - Maniar, Alok
AU  - Maniar A
AD  - Merck & Co. Inc, Rahway, NJ, USA.
FAU - Zhang, Ying
AU  - Zhang Y
AD  - Merck & Co. Inc, Rahway, NJ, USA.
FAU - Paschke, Amanda
AU  - Paschke A
AD  - Merck & Co. Inc, Rahway, NJ, USA.
FAU - Chen, Luke F
AU  - Chen LF
AD  - Merck & Co. Inc, Rahway, NJ, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03230916
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230902
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - Y1MYA2UHFL (relebactam)
RN  - 71OTZ9ZE0A (Imipenem)
RN  - 141A6AMN38 (Cilastatin)
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Azabicyclo Compounds)
RN  - 0 (Drug Combinations)
SB  - IM
MH  - Adult
MH  - Child
MH  - Humans
MH  - Imipenem/pharmacokinetics
MH  - Cilastatin/adverse effects/pharmacokinetics
MH  - Anti-Bacterial Agents
MH  - Azabicyclo Compounds/adverse effects
MH  - Drug Combinations
MH  - *Gram-Negative Bacterial Infections/drug therapy
MH  - Microbial Sensitivity Tests
MH  - *Bacterial Infections/drug therapy
OTO - NOTNLM
OT  - carbapenem/beta-lactamase inhibitor
OT  - children
OT  - dose selection
OT  - gram-negative bacterial infection
OT  - imipenem/cilastatin/relebactam
EDAT- 2023/08/10 18:41
MHDA- 2023/11/10 06:45
CRDT- 2023/08/10 17:32
PHST- 2023/04/18 00:00 [received]
PHST- 2023/08/02 00:00 [accepted]
PHST- 2023/11/10 06:45 [medline]
PHST- 2023/08/10 18:41 [pubmed]
PHST- 2023/08/10 17:32 [entrez]
AID - 10.1002/jcph.2334 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2023 Dec;63(12):1387-1397. doi: 10.1002/jcph.2334. Epub 2023 
      Sep 2.