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.
carbapenem/β-lactamase inhibitor
children
dose selection
gram-negative bacterial infection
imipenem/cilastatin/relebactam
Journal
Journal of clinical pharmacology
ISSN: 1552-4604
Titre abrégé: J Clin Pharmacol
Pays: England
ID NLM: 0366372
Informations de publication
Date de publication:
12 2023
12 2023
Historique:
received:
18
04
2023
accepted:
02
08
2023
medline:
10
11
2023
pubmed:
10
8
2023
entrez:
10
8
2023
Statut:
ppublish
Résumé
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
Substances chimiques
relebactam
Y1MYA2UHFL
Imipenem
71OTZ9ZE0A
Cilastatin
141A6AMN38
Anti-Bacterial Agents
0
Azabicyclo Compounds
0
Drug Combinations
0
Banques de données
ClinicalTrials.gov
['NCT03230916']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1387-1397Informations de copyright
© 2023 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.
Références
Meropol SB, Haupt AA, Debanne SM. Incidence and outcomes of infections caused by multidrug-resistant Enterobacteriaceae in children, 2007-2015. J Pediatric Infect Dis Soc. 2018;7(1):36-45.
Chiotos K, Tamma PD, Flett KB, et al. Increased 30-day mortality associated with carbapenem-resistant Enterobacteriaceae in children. Open Forum Infect Dis. 2018;5(10):ofy222.
Maltezou HC, Kontopidou F, Katerelos P, Daikos G, Roilides E, Theodoridou M. Infections caused by carbapenem-resistant Gram-negative pathogens in hospitalized children. Pediatr Infect Dis J. 2013;32(4):e151-e154.
World Health Organization. WHO publishes list of bacteria for which new antibiotics are urgently needed. Accessed April 18, 2022. https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed
Karlowsky JA, Lob SH, Raddatz J, et al. In vitro activity of imipenem/relebactam and ceftolozane/tazobactam against clinical isolates of Gram-negative bacilli with difficult-to-treat resistance and multidrug-resistant phenotypes-study for monitoring antimicrobial resistance trends, United States 2015-2017. Clin Infect Dis. 2021;72(12):2112-2120.
Theuretzbacher U. Global antimicrobial resistance in Gram-negative pathogens and clinical need. Curr Opin Microbiol. 2017;39:106-112.
Center for Disease Control and Prevention. Antibiotic resistance threats in the United States 2019. Accessed August 18, 2023. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf.
Motsch J, Murta de Oliveira C, Stus V, et al. RESTORE-IMI 1: a multicenter, randomized, double-blind trial comparing efficacy and safety of imipenem/relebactam vs colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections. Clin Infect Dis. 2020;70(9):1799-1808.
RECARBRIO™ (Imipenem/Cilastatin and Relebactam). US prescribing information. Merck Sharp & Dohme LLC; 2022.
Titov I, Wunderink RG, Roquilly A, et al. A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 study). Clin Infect Dis. 2020;ciaa803.
Karlowsky JA, Lob SH, Kazmierczak KM, et al. In vitro activity of imipenem/relebactam against Gram-negative ESKAPE pathogens isolated in 17 European countries: 2015 SMART surveillance programme. J Antimicrob Chemother. 2018;73(7):1872-1879.
Karlowsky JA, Lob SH, Young K, Motyl MR, Sahm DF. In vitro activity of imipenem/relebactam against gram-negative bacilli from pediatric patients-Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance program 2015-2017. J Pediatric Infect Dis Soc. 2021;10(3):274-281.
Karlowsky JA, Lob SH, Young K, Motyl MR, Sahm DF. Activity of imipenem-relebactam against multidrug-resistant Pseudomonas aeruginosa from the United States - SMART 2015-2017. Diagn Microbiol Infect Dis. 2019;95(2):212-215.
Rhee EG, Rizk ML, Calder N, et al. Pharmacokinetics, safety, and tolerability of single and multiple doses of relebactam, a β-lactamase inhibitor, in combination with imipenem and cilastatin in healthy participants. Antimicrob Agents Chemother. 2018;62(9):e00280-18.
Patel M, Bellanti F, Daryani NM, et al. Population pharmacokinetic/pharmacodynamic assessment of imipenem/cilastatin/relebactam in patients with hospital-acquired/ventilator-associated bacterial pneumonia. Clin Transl Sci. 2022;15(2):396-408.
Fernandez E, Perez R, Hernandez A, Tejada P, Arteta M, Ramos JT. Factors and mechanisms for pharmacokinetic differences between pediatric population and adults. Pharmaceutics. 2011;3(1):53-72.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41.
Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3):629-637.
Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in full-term infants during the first year of life. J Pediatr. 1984;104(6):849-854.
Ambrose PG, Bhavnani SM, Rubino CM, et al. Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it's not just for mice anymore. Clin Infect Dis. 2007;44(1):79-86.
Lala M, Brown M, Kantesaria B, Walker B, Paschke A, Rizk ML. Simplification of imipenem dosing by removal of weight-based adjustments. J Clin Pharmacol. 2019;59(5):646-653.
Bhagunde P, Patel P, Lala M, et al. Population pharmacokinetic analysis for imipenem-relebactam in healthy volunteers and patients with bacterial infections. CPT: Pharmacometrics Syst Pharmacol. 2019;8(10):748-758.
Vaddady P, Bhagunde P, Xu M, et al. Application of Bayesian methodology to inform imipenem/relebactam pediatric study design. Presented at: Population Approach Group Europe (PAGE); June 11-14, 2019; Stockholm, Sweden.
Center for Disease Control and Prevention. National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Accessed August 18, 2023. https://wwwn.cdc.gov/nchs/nhanes/Default.aspx
Savory D. Reference ranges for serum creatinine in infants, children and adolescents. Ann Clin Biochem. 1990;27(2):99-101.
Daryani N, Patel M, Flattery A, Young K, Rizk ML. Imipenem/relebactam pharmacokinetic/pharmacodynamic analyses from an in vivo neutropenic mouse delayed lung infection model [abstract 2086]. Presented at: European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); April 18-21, 2020; Paris, France.
Patel M, Daryani NM, Feng H-P, et al. Imipenem/relebactam pharmacokinetic/pharmacodynamic analyses from an in vivo neutropenic murine thigh infection model [abstract 1693]. Presented at: European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); April 18-21, 2020; Paris, France.
O'Donnell JN, Lodise TP. New perspectives on antimicrobial agents: imipenem-relebactam. Antimicrob Agents Chemother. 2022;66(7):e0025622.
van den Anker J, Reed MD, Allegaert K, Kearns GL. Developmental changes in pharmacokinetics and pharmacodynamics. J Clin Pharmacol. 2018;58(suppl 10):S10-S25.
Livermore DM, Warner M, Mushtaq S. Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J Antimicrob Chemother. 2013;68(10):2286-2290.
Young K, Painter RE, Raghoobar SL, et al. In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa. BMC Microbiol. 2019;19(1):150.
Horner C, Mushtaq S, Livermore DM. Potentiation of imipenem by relebactam for Pseudomonas aeruginosa from bacteraemia and respiratory infections. J Antimicrob Chemother. 2019;74(7):1940-1944.
Wu J, Racine F, Wismer MK, et al. Exploring the pharmacokinetic/pharmacodynamic relationship of relebactam (MK-7655) in combination with imipenem in a hollow-fiber infection model. Antimicrob Agents Chemother. 2018;62:e0232317.
Mavridou E, Melchers RJ, van Mil AC, Mangin E, Motyl MR, Mouton JW. Pharmacodynamics of imipenem in combination with β-lactamase inhibitor MK7655 in a murine thigh model. Antimicrob Agents Chemother. 2015;59(2):790-795.
Bhagunde P, Zhang Z, Racine F, et al. A translational pharmacokinetic/pharmacodynamic model to characterize bacterial kill in the presence of imipenem-relebactam. Int J Infect Dis. 2019;89:55-61.
Coppini R, Simons SHP, Mugelli A, Allegaert K. Clinical research in neonates and infants: challenges and perspectives. Pharmacol Res. 2016;108:80-87.