Thorough QTc Study of a Single Supratherapeutic Dose of Relebactam in Healthy Participants.
antibiotic
cardiac safety
phase 1
relebactam
β-lactamase inhibitor
Journal
Clinical pharmacology in drug development
ISSN: 2160-7648
Titre abrégé: Clin Pharmacol Drug Dev
Pays: United States
ID NLM: 101572899
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
30
05
2019
accepted:
02
02
2020
pubmed:
27
3
2020
medline:
6
5
2022
entrez:
27
3
2020
Statut:
ppublish
Résumé
The effects of supratherapeutic doses of intravenous (IV) relebactam on duration of ventricular depolarization and subsequent repolarization were assessed in a thorough QT/corrected QT study. This was a single-dose, double-blind (relebactam only), randomized, placebo- and positive-controlled, 3-period, balanced crossover study in healthy participants. Participants received in randomized order, and separated by a washout (≥4 days), a single dose of IV relebactam 1150 mg, oral moxifloxacin 400 mg (open-label positive control), and IV placebo. Least squares mean and 2-sided 90% confidence interval for change from baseline in population-derived corrected QT intervals for relebactam, moxifloxacin, and placebo were estimated for 24 hours. The upper limit of the 90% confidence interval of all least squares mean population-derived corrected QT treatment differences from placebo was not >10 milliseconds at any time point for 24 hours. Corrected QT assay sensitivity was confirmed with moxifloxacin treatment. Analysis of electrocardiogram parameters resulted in no additional cardiac safety concerns. Overall, a supratherapeutic dose of relebactam yielded no cardiac safety events; the 1150-mg supratherapeutic dose (4.6-fold above the 250-mg therapeutic dose) was not associated with QT prolongation or other abnormal cardiodynamic parameters. This study lends additional support to relebactam's use as a β-lactamase inhibitor in antimicrobial therapy.
Substances chimiques
Azabicyclo Compounds
0
Moxifloxacin
U188XYD42P
relebactam
Y1MYA2UHFL
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
466-475Subventions
Organisme : Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA
Informations de copyright
© 2020, The American College of Clinical Pharmacology.
Références
Drawz SM, Papp-Wallace KM, Bonomo RA. New beta-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother. 2014;58(4):1835-1846.
Mangion IK, Ruck RT, Rivera N, Huffman MA, Shevlin M. A concise synthesis of a beta-lactamase inhibitor. Org Lett. 2011;13(20):5480-5483.
Zhanel GG, Lawrence CK, Adam H, et al. Imipenem-relebactam and meropenem-vaborbactam: two novel carbapenem-beta-lactamase inhibitor combinations. Drugs. 2018;78(1):65-98.
Hirsch EB, Ledesma KR, Chang KT, Schwartz MS, Motyl MR, Tam VH. In vitro activity of MK-7655, a novel beta-lactamase inhibitor, in combination with imipenem against carbapenem-resistant gram-negative bacteria. Antimicrob Agents Chemother. 2012;56(7):3753-3757.
Lapuebla A, Abdallah M, Olafisoye O, et al. Activity of imipenem with relebactam against gram-negative pathogens from New York City. Antimicrob Agents Chemother. 2015;59(8):5029-5031.
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.
Lob SH, Hackel MA, Kazmierczak KM, et al. In vitro activity of imipenem-relebactam against gram-negative ESKAPE pathogens isolated by clinical laboratories in the United States in 2015 (results from the SMART global surveillance program). Antimicrob Agents Chemother. 2017;61(6):e02209-16.
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 [published online ahead of print August 10, 2019]. Clin Infect Dis. https://doi.org/10.1093/cid/ciz530.
Lucasti C, Vasile L, Sandesc D, et al. Phase 2, dose-ranging study of relebactam with imipenem-cilastatin in subjects with complicated intra-abdominal infection. Antimicrob Agents Chemother. 2016;60(10):6234-6243.
Sims M, Mariyanovski V, McLeroth P, et al. Prospective, randomized, double-blind, phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. J Antimicrob Chemother. 2017;72(9):2616-2626.
Rhee EG, Rizk ML, Calder N, et al. Pharmacokinetics, safety, and tolerability of single and multiple doses of relebactam, a beta-lactamase inhibitor, in combination with imipenem and cilastatin in healthy participants. Antimicrob Agents Chemother. 2018;62(9):e00280-18.
US Food and Drug Administration. E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs https://www.ncbi.nlm.nih.gov/pubmed/16237860. Published 2005. Accessed May 21, 2019.
ICH Expert Working Group. ICH Harmonised Tripartite Guideline. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. https://www.ema.europa.eu/documents/scientific-guideline/ich-e-14-clinical-evaluation-qt/qts-interval-prolongation-proarrhythmic-potential-non-antiarrhythmic-drugs-step-5_en.pdf. Published 2005. Accessed July 10, 2019.
Owens RC, Jr., Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis. 2006;43(12):1603-1611.
Pollard CE, Valentin JP, Hammond TG. Strategies to reduce the risk of drug-induced QT interval prolongation: a pharmaceutical company perspective. Br J Pharmacol. 2008;154(7):1538-1543.
Tisdale JE. Drug-induced QT interval prolongation and torsades de pointes: role of the pharmacist in risk assessment, prevention and management. Can Pharm J (Ott). 2016;149(3):139-152.
Garnett C, Bonate PL, Dang Q, et al. Scientific white paper on concentration-QTc modeling. J Pharmacokinet Pharmacodyn. 2018;45(3):383-397.
Kenward M, Roger J. Effect of maize silage to grass silage ratio and feed particle size on protein synthesis and amino acid profile in different microbial fractions in a semi-continuous rumen simulation. Biometrics. 1997;53:983-997.
Keller GA, Alvarez PA, Ponte ML, et al. Drug-induced QTc interval prolongation: a multicenter study to detect drugs and clinical factors involved in every day practice. Curr Drug Saf. 2016;11(1):86-98.
Das S, Armstrong J, Mathews D, Li J, Edeki T. Randomized, placebo-controlled study to assess the impact on QT/QTc interval of supratherapeutic doses of ceftazidime-avibactam or ceftaroline fosamil-avibactam. J Clin Pharmacol. 2014;54(3):331-340.
Rodloff A, Goldstein E, Torres A. Two decades of imipenem therapy. J Antimicrob Chemother. 2006;58(5):916-929.