دورية أكاديمية
Safety and Pharmacokinetic Characterization of Nacubactam, a Novel β-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers.
| العنوان: | Safety and Pharmacokinetic Characterization of Nacubactam, a Novel β-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers. |
|---|---|
| المؤلفون: | Mallalieu NL; Roche Innovation Center, New York, New York, USA., Winter E; Roche Innovation Center, New York, New York, USA., Fettner S; Roche Innovation Center, New York, New York, USA., Patel K; Roche Innovation Center, Welwyn, United Kingdom., Zwanziger E; Roche Innovation Center, Basel, Switzerland., Attley G; Roche Innovation Center, New York, New York, USA., Rodriguez I; Roche Innovation Center, New York, New York, USA., Kano A; Meiji Seika Pharma Co., Ltd., Tokyo, Japan., Salama SM; Fedora Pharmaceuticals, Inc., Edmonton, Alberta, Canada., Bentley D; Roche Innovation Center, Welwyn, United Kingdom., Geretti AM; Roche Innovation Center, Basel, Switzerland anna_maria.geretti@roche.com.; Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom. |
| المصدر: | Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2020 Apr 21; Vol. 64 (5). Date of Electronic Publication: 2020 Apr 21 (Print Publication: 2020). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 0315061 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-6596 (Electronic) Linking ISSN: 00664804 NLM ISO Abbreviation: Antimicrob Agents Chemother Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, American Society for Microbiology |
| مواضيع طبية MeSH: | Anti-Bacterial Agents/*adverse effects , Anti-Bacterial Agents/*pharmacokinetics , Azabicyclo Compounds/*adverse effects , Azabicyclo Compounds/*pharmacokinetics , Lactams/*adverse effects , Lactams/*pharmacokinetics , Meropenem/*adverse effects , Meropenem/*pharmacokinetics , beta-Lactamase Inhibitors/*adverse effects , beta-Lactamase Inhibitors/*pharmacokinetics, Adolescent ; Adult ; Aged ; Area Under Curve ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Combinations ; Drug Interactions ; Electrocardiography/drug effects ; Female ; Humans ; Male ; Middle Aged ; Patient Safety ; Young Adult |
| مستخلص: | Nacubactam is a novel β-lactamase inhibitor with dual mechanisms of action as an inhibitor of serine β-lactamases (classes A and C and some class D) and an inhibitor of penicillin binding protein 2 in Enterobacteriaceae The safety, tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in single- and multiple-ascending-dose, placebo-controlled studies. Healthy participants received single ascending doses of nacubactam of 50 to 8,000 mg, multiple ascending doses of nacubactam of 1,000 to 4,000 mg every 8 h (q8h) for up to 7 days, or nacubactam of 2,000 mg plus meropenem of 2,000 mg q8h for 6 days after a 3-day lead-in period. Nacubactam was generally well tolerated, with the most frequently reported adverse events (AEs) being mild to moderate complications associated with intravenous access and headache. There was no apparent relationship between drug dose and the pattern, incidence, or severity of AEs. No clinically relevant dose-related trends were observed in laboratory safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. After single or multiple doses, nacubactam pharmacokinetics appeared linear, and exposure increased in an approximately dose-proportional manner across the dose range investigated. Nacubactam was excreted largely unchanged into urine. Coadministration of nacubactam with meropenem did not significantly alter the pharmacokinetics of either drug. These findings support the continued clinical development of nacubactam and demonstrate the suitability of meropenem as a potential β-lactam partner for nacubactam. (The studies described in this paper have been registered at ClinicalTrials.gov under NCT02134834 [single ascending dose study] and NCT02972255 [multiple ascending dose study].). (Copyright © 2020 Mallalieu et al.) |
| References: | Antimicrob Agents Chemother. 2015 Nov 09;60(1):554-60. (PMID: 26552987) Antimicrob Agents Chemother. 2017 Sep 22;61(10):. (PMID: 28760891) J Antimicrob Chemother. 2015 Oct;70(10):2779-86. (PMID: 26089439) Antimicrob Agents Chemother. 2016 Sep 23;60(10):6326-32. (PMID: 27527080) Pharmacotherapy. 2006 Sep;26(9):1320-32. (PMID: 16945055) Antimicrob Agents Chemother. 2018 Aug 27;62(9):. (PMID: 29914955) Antimicrob Agents Chemother. 2018 Mar 27;62(4):. (PMID: 29437614) J Antimicrob Chemother. 2015 Nov;70(11):3032-41. (PMID: 26311835) Clin Pharmacol Ther. 2015 Apr;97(4):326-35. (PMID: 25670536) Am Fam Physician. 2008 Sep 15;78(6):743-50. (PMID: 18819242) Clin Pharmacol Ther. 2015 Dec;98(6):630-8. (PMID: 26259519) Pediatr Nephrol. 1997 Dec;11(6):768-72. (PMID: 9438663) Clin Drug Investig. 2015 May;35(5):307-17. (PMID: 25813217) |
| معلومات مُعتمدة: | HHSO100201600038C United States HH HHS |
| فهرسة مساهمة: | Keywords: beta-lactam; beta-lactamase inhibitor; meropenem; multiple ascending dose; nacubactam; pharmacokinetics; phase I; single ascending dose |
| سلسلة جزيئية: | ClinicalTrials.gov NCT02134834; NCT02972255 |
| المشرفين على المادة: | 0 (Anti-Bacterial Agents) 0 (Azabicyclo Compounds) 0 (Drug Combinations) 0 (Lactams) 0 (beta-Lactamase Inhibitors) 832O37V7MZ (nacubactam) FV9J3JU8B1 (Meropenem) |
| تواريخ الأحداث: | Date Created: 20200212 Date Completed: 20210405 Latest Revision: 20210413 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC7179653 |
| DOI: | 10.1128/AAC.02229-19 |
| PMID: | 32041717 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1098-6596 |
|---|---|
| DOI: | 10.1128/AAC.02229-19 |