دورية أكاديمية
Dose selection for a phase III study evaluating gepotidacin (GSK2140944) in the treatment of uncomplicated urogenital gonorrhoea.
| العنوان: | Dose selection for a phase III study evaluating gepotidacin (GSK2140944) in the treatment of uncomplicated urogenital gonorrhoea. |
|---|---|
| المؤلفون: | Scangarella-Oman NE; GSK Collegeville, Collegeville, Pennsylvania, USA nicole.e.scangarella-oman@gsk.com., Hossain M; GSK Collegeville, Collegeville, Pennsylvania, USA., Perry CR; GSK Collegeville, Collegeville, Pennsylvania, USA., Tiffany C; GSK Collegeville, Collegeville, Pennsylvania, USA., Powell M; GSK, Research Triangle Park, North Carolina, USA., Swift B; GSK, Research Triangle Park, North Carolina, USA., Dumont EF; GSK Collegeville, Collegeville, Pennsylvania, USA. |
| المصدر: | Sexually transmitted infections [Sex Transm Infect] 2023 Feb; Vol. 99 (1), pp. 64-69. Date of Electronic Publication: 2022 Nov 21. |
| نوع المنشور: | Journal Article; Review; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: BMJ Pub. Group Country of Publication: England NLM ID: 9805554 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1472-3263 (Electronic) Linking ISSN: 13684973 NLM ISO Abbreviation: Sex Transm Infect Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: London : BMJ Pub. Group, c1998- |
| مواضيع طبية MeSH: | Gonorrhea*/drug therapy , Gonorrhea*/microbiology, Humans ; Acetylcholinesterase/pharmacology ; Acetylcholinesterase/therapeutic use ; Anti-Bacterial Agents/therapeutic use ; Acenaphthenes/pharmacology ; Acenaphthenes/therapeutic use ; Neisseria gonorrhoeae ; Microbial Sensitivity Tests ; Clinical Trials, Phase III as Topic |
| مستخلص: | Background: Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and is active against most strains of Neisseria gonorrhoeae ( N. gonorrhoeae ). Phase II data suggested higher exposures were needed for efficacy and to suppress resistance development. A translational approach using in vitro pharmacokinetic/pharmacodynamic (PK/PD) and clinical data was used to select a gepotidacin dose for a phase III study. In this narrative review of previously shown data, we summarise how a translational approach based on in vitro PK/PD and population PK modelling and simulation data was undertaken to select a dosing regimen for the ongoing phase III gepotidacin study in participants with uncomplicated urogenital gonorrhoea. Methods: For dose selection, prior in vitro minimum inhibitory concentrations (MICs) and PK/PD data were available. PK modelling was conducted to determine a dose that would limit plasma concentrations to less than 14 µg/mL (as concentrations above this are associated with QT prolongation and effects associated with acetylcholinesterase inhibition) while maintaining ≥90% probability of target attainment (PTA) for efficacy and resistance suppression against N. gonorrhoeae isolates with gepotidacin MICs ≤1 µg/mL. Results: Two 3000 mg gepotidacin doses, administered 10-12 hours apart, resulted in PTA of ≥97.5% and ≥91.7% for gepotidacin MICs ≤1 µg/mL for the ratio of the area under the free drug plasma concentration-time curve over 24 hours to the MIC ( f AUC Conclusions: Two gepotidacin 3000 mg oral doses 10-12 hours apart provide ~2-fold higher systemic exposures, increase efficacy for higher gepotidacin MIC N. gonorrhoeae isolates, reduce resistance potential and limit plasma concentrations of potential safety concern, compared with higher doses. Competing Interests: Competing interests: All authors report employment with and stock/share options in GSK at the time of the study. MH is currently employed by Servier Pharmaceuticals, Boston, Massachusetts, USA. CT is currently employed by Spark Therapeutics, Philadelphia, Pennsylvania, USA. EFD is currently employed by Boston Pharmaceuticals, Cambridge, Massachusetts, USA. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) |
| References: | J Antimicrob Chemother. 2018 Aug 1;73(8):2072-2077. (PMID: 29796611) MMWR Recomm Rep. 2021 Jul 23;70(4):1-187. (PMID: 34292926) ACS Infect Dis. 2019 Apr 12;5(4):570-581. (PMID: 30757898) Antimicrob Agents Chemother. 2018 Nov 26;62(12):. (PMID: 30249694) Euro Surveill. 2020 Oct;25(43):. (PMID: 33124551) Ther Clin Risk Manag. 2008 Feb;4(1):269-86. (PMID: 18728716) Antimicrob Agents Chemother. 2017 Jan 24;61(2):. (PMID: 27872075) Nature. 2010 Aug 19;466(7309):935-40. (PMID: 20686482) Antimicrob Agents Chemother. 2017 Apr 24;61(5):. (PMID: 28223381) PLoS Med. 2017 Jul 7;14(7):e1002344. (PMID: 28686231) Clin Infect Dis. 2018 Aug 1;67(4):504-512. (PMID: 29617982) MMWR Morb Mortal Wkly Rep. 2020 Dec 18;69(50):1911-1916. (PMID: 33332296) Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0126321. (PMID: 34633853) Clin Infect Dis. 2007 Jan 1;44(1):79-86. (PMID: 17143821) Clin Microbiol Infect. 2019 Jan;25(1):48-53. (PMID: 29777927) Antimicrob Agents Chemother. 2020 Jun 23;64(7):. (PMID: 32284384) Antimicrob Agents Chemother. 2020 Sep 21;64(10):. (PMID: 32661002) Antimicrob Agents Chemother. 2019 Feb 26;63(3):. (PMID: 30642924) Clin Microbiol Rev. 2014 Jul;27(3):587-613. (PMID: 24982323) Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0012221. (PMID: 34543096) PLoS One. 2015 Jan 05;10(1):e0116207. (PMID: 25559848) Philos Trans R Soc Lond B Biol Sci. 1999 Apr 29;354(1384):787-97. (PMID: 10365404) Antimicrob Agents Chemother. 2017 Feb 23;61(3):. (PMID: 28069643) |
| فهرسة مساهمة: | Keywords: clinical trial; gonorrhoea; neisseria gonorrhoeae |
| سلسلة جزيئية: | ClinicalTrials.gov NCT02294682 |
| المشرفين على المادة: | DVF0PR037D (gepotidacin) EC 3.1.1.7 (Acetylcholinesterase) 0 (Anti-Bacterial Agents) 0 (Acenaphthenes) |
| تواريخ الأحداث: | Date Created: 20221121 Date Completed: 20230119 Latest Revision: 20230208 |
| رمز التحديث: | 20230208 |
| مُعرف محوري في PubMed: | PMC9887395 |
| DOI: | 10.1136/sextrans-2022-055518 |
| PMID: | 36411033 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1472-3263 |
|---|---|
| DOI: | 10.1136/sextrans-2022-055518 |