{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:40:29Z","timestamp":1792798829403,"version":"4.5.0"},"reference-count":37,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T00:00:00Z","timestamp":1668988800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"GSK","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]},{"name":"Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority","award":["HHSO100201300011C"],"award-info":[{"award-number":["HHSO100201300011C"]}],"id":[{"id":"https:\/\/ror.org\/029y69023","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Sex Transm Infect"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>Neisseria gonorrhoeae<\/jats:italic>\n                      (\n                      <jats:italic>N. gonorrhoeae<\/jats:italic>\n                      ). 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\u2009\u00b5g\/mL (as concentrations above this are associated with QT prolongation and effects associated with acetylcholinesterase inhibition) while maintaining \u226590% probability of target attainment (PTA) for efficacy and resistance suppression against\n                      <jats:italic>N. gonorrhoeae<\/jats:italic>\n                      isolates with gepotidacin MICs \u22641\u2009\u00b5g\/mL.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Two 3000\u2009mg gepotidacin doses, administered 10\u201312 hours apart, resulted in PTA of \u226597.5%\u2009and \u226591.7% for gepotidacin MICs \u22641\u2009\u00b5g\/mL for the ratio of the area under the free drug plasma concentration\u2013time curve over 24 hours to the MIC (\n                      <jats:italic>f<\/jats:italic>\n                      AUC\n                      <jats:sub>0\u201324<\/jats:sub>\n                      \/MIC) efficacy, and resistance suppression targets of 40 and 46, respectively, but limited the occurrence of maximum plasma concentrations \u226514\u2009\u00b5g\/mL.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Two gepotidacin 3000\u2009mg oral doses 10\u201312\u2009hours apart provide ~2-fold higher systemic exposures, increase efficacy for higher gepotidacin MIC\n                      <jats:italic>N. gonorrhoeae<\/jats:italic>\n                      isolates, reduce resistance potential and limit plasma concentrations of potential safety concern, compared with higher doses.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/sextrans-2022-055518","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T13:20:23Z","timestamp":1669036823000},"page":"64-69","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Dose selection for a phase III study evaluating gepotidacin (GSK2140944) in the treatment of uncomplicated urogenital gonorrhoea"],"prefix":"10.1136","volume":"99","clinical-trial-number":[{"clinical-trial-number":"nct02294682","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04010539","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04079790","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02257398","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04079790","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04010539","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02294682","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04010539","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4211-8261","authenticated-orcid":false,"given":"Nicole E","family":"Scangarella-Oman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Hossain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline R","family":"Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Tiffany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcy","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Swift","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne F","family":"Dumont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,11,21]]},"reference":[{"key":"2023101000001321000_99.1.64.1","unstructured":"World Health Organization . Sexually transmitted infections (STIs), 2021. Available: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/sexually-transmitted-infections-(stis) [Accessed 3 Mar 2022]."},{"key":"2023101000001321000_99.1.64.2","unstructured":"Centers for Disease Control and Prevention . Sexually transmitted disease surveillance 2018, 2019. Available: https:\/\/www.cdc.gov\/std\/stats18\/STDSurveillance2018-full-report.pdf [Accessed 13 Oct 2021]."},{"key":"2023101000001321000_99.1.64.3","unstructured":"Centers for Disease Control and Prevention . Antibiotic resistance threats in the United States, 2019. Available: https:\/\/www.cdc.gov\/drugresistance\/pdf\/threats-report\/2019-ar-threats-report-508.pdf"},{"key":"2023101000001321000_99.1.64.4","unstructured":"World Health Organization . Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics, 2017. Available: https:\/\/www.who.int\/medicines\/publications\/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf [Accessed 1 Mar 2022]."},{"key":"2023101000001321000_99.1.64.5","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00010-14"},{"key":"2023101000001321000_99.1.64.6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002344"},{"key":"2023101000001321000_99.1.64.7","unstructured":"World Health Organization . WHO guidelines for the treatment of Neisseria gonorrhoeae, 2016. Available: https:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/246114\/9789241549691-eng.pdf"},{"key":"2023101000001321000_99.1.64.8","unstructured":"World Health Organization . WHO global action plan to control the spread and impact of antimicrobial resistance in Neiserria gonorrhoeae, 2012. Available: http:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/44863\/9789241503501_eng.pdf?sequence=1"},{"key":"2023101000001321000_99.1.64.9","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6950a6"},{"key":"2023101000001321000_99.1.64.10","unstructured":"European Centre for Disease Prevention and Control . Gonorrhoea - annual epidemiological report for 2018, 2020. Available: https:\/\/www.ecdc.europa.eu\/en\/publications-data\/gonorrhoea-annual-epidemiological-report-2018"},{"key":"2023101000001321000_99.1.64.11","doi-asserted-by":"crossref","first-page":"e01644","DOI":"10.1128\/AAC.01644-18","article-title":"Pharmacokinetic Data Are Predictive of In Vivo Efficacy for Cefixime and Ceftriaxone against Susceptible and Resistant Neisseria gonorrhoeae Strains in the Gonorrhea Mouse Model","volume":"63","author":"Connolly","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2023101000001321000_99.1.64.12","doi-asserted-by":"crossref","first-page":"S792","DOI":"10.1093\/ofid\/ofab466.1607","article-title":"1415. allergies to antimicrobial agents among US females with uncomplicated urinary tract infection","volume":"8","author":"Thompson","year":"2021","journal-title":"Open Forum Infect Dis"},{"key":"2023101000001321000_99.1.64.13","unstructured":"World Health Organization . Antibiotic-resistant gonorrhoea on the rise, new drugs needed, 2017. Available: https:\/\/www.who.int\/news\/item\/07-07-2017-antibiotic-resistant-gonorrhoea-on-the-rise-new-drugs-needed [Accessed Nov 2021]."},{"key":"2023101000001321000_99.1.64.14","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1021\/acsinfecdis.8b00315","article-title":"Mechanistic and structural basis for the actions of the antibacterial gepotidacin against Staphylococcus aureus gyrase","volume":"5","author":"Gibson","year":"2019","journal-title":"ACS Infect Dis"},{"key":"2023101000001321000_99.1.64.15","doi-asserted-by":"publisher","DOI":"10.1038\/nature09197"},{"key":"2023101000001321000_99.1.64.16","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dky162"},{"key":"2023101000001321000_99.1.64.17","doi-asserted-by":"crossref","first-page":"e02047","DOI":"10.1128\/AAC.02047-16","article-title":"In vitro activity of gepotidacin (GSK2140944) against Neisseria gonorrhoeae","volume":"61","author":"Farrell","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2023101000001321000_99.1.64.18","unstructured":"Mushtaq S , Vickers A , Sadouki Z . In-vitro activities of gepotidacin, a novel triazaacenaphthylene and topoisomerase IV DNA gyrase inhibitor, against gram-negative bacteria and Staphylococcus saprophyticus. Poster p1849. Amsterdam, The Netherlands ECCMID; 2019."},{"key":"2023101000001321000_99.1.64.19","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciy145"},{"key":"2023101000001321000_99.1.64.20","doi-asserted-by":"publisher","DOI":"10.1086\/510079"},{"key":"2023101000001321000_99.1.64.21","doi-asserted-by":"crossref","first-page":"e01221","DOI":"10.1128\/AAC.01221-18","article-title":"Microbiological analysis from a phase 2 randomized study in adults evaluating single oral doses of gepotidacin in the treatment of uncomplicated urogenital gonorrhea caused by Neisseria gonorrhoeae","volume":"62","author":"Scangarella-Oman","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2023101000001321000_99.1.64.22","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00115-16"},{"key":"2023101000001321000_99.1.64.23","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.00122-21","article-title":"Gepotidacin pharmacokinetics-pharmacodynamics against Escherichia coli in the one-compartment and hollow-fiber in vitro infection model systems","volume":"65","author":"VanScoy","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"key":"2023101000001321000_99.1.64.24","unstructured":"Singh R , Dumont E , Powell M , et al . Assessing safety and efficacy to determine the gepotidacin probability of pharmacological success in urogenital gonorrhea. Presented at the 12th Annual Congress of the American Conference on Pharmacometrics, 2021."},{"key":"2023101000001321000_99.1.64.25","doi-asserted-by":"crossref","first-page":"S794","DOI":"10.1093\/ofid\/ofab466.1614","article-title":"1422. real-world study of the effects of inappropriate or suboptimal treatment on the burden of illness among patients with uncomplicated urinary tract infection and high-risk comorbid conditions in the United States","volume":"8","author":"Preib","year":"2021","journal-title":"Open Forum Infect Dis"},{"key":"2023101000001321000_99.1.64.26","doi-asserted-by":"crossref","first-page":"1900210","DOI":"10.2807\/1560-7917.ES.2020.25.43.1900210","article-title":"Using rapid point-of-care tests to inform antibiotic choice to mitigate drug resistance in gonorrhoea","volume":"25","author":"Vegvari","year":"2020","journal-title":"Euro Surveill"},{"key":"2023101000001321000_99.1.64.27","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.1999.0431"},{"key":"2023101000001321000_99.1.64.28","doi-asserted-by":"crossref","first-page":"e00199","DOI":"10.1128\/AAC.00199-20","article-title":"Phase 2a pharmacokinetic, safety, and exploratory efficacy evaluation of oral gepotidacin (GSK2140944) in female participants with uncomplicated urinary tract infection (acute uncomplicated cystitis)","volume":"64","author":"Overcash","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"key":"2023101000001321000_99.1.64.29","doi-asserted-by":"crossref","first-page":"e02385","DOI":"10.1128\/AAC.02385-16","article-title":"A phase I, randomized, double-blinded, placebo- and moxifloxacin-controlled, four-period crossover study to evaluate the effect of gepotidacin on cardiac conduction as assessed by 12-lead electrocardiogram in healthy volunteers","volume":"61","author":"Hossain","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2023101000001321000_99.1.64.30","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01263-21","article-title":"Pharmacokinetics of oral formulations of gepotidacin (GSK2140944), a triazaacenaphthylene bacterial type II topoisomerase inhibitor, in healthy adult and adolescent participants","volume":"66","author":"Barth","year":"2022","journal-title":"Antimicrob Agents Chemother"},{"key":"2023101000001321000_99.1.64.31","doi-asserted-by":"crossref","first-page":"e00521","DOI":"10.1128\/AAC.00521-20","article-title":"Relationship between gepotidacin exposure and prevention of on-therapy resistance amplification in a Neisseria gonorrhoeae hollow-fiber in vitro infection model","volume":"64","author":"VanScoy","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"key":"2023101000001321000_99.1.64.32","unstructured":"Scangarella-Oman N , Hossain M , Perry C , et al . Dose selection for a phase 3 study evaluating gepotidacin (GSK2140944) in the treatment of gonorrhoea. Presented at the 31st Annual Congress of the European Society for Clinical Microbiology and Infectious Diseases, virtual, 9\u201314 July, 2021."},{"key":"2023101000001321000_99.1.64.33","unstructured":"ClinicalTrials.gov . NCT04010539. A study to evaluate efficacy and safety of gepotidacin compared with ceftriaxone plus azithromycin in the treatment of uncomplicated urogenital gonorrhea, 2019. Available: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04010539 [Accessed Nov 2021]."},{"key":"2023101000001321000_99.1.64.34","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.rr7005a1"},{"key":"2023101000001321000_99.1.64.35","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0116207","article-title":"Compliance with once-daily versus twice or thrice-daily administration of antibiotic regimens: a meta-analysis of randomized controlled trials","volume":"10","author":"Falagas","year":"2015","journal-title":"PLoS One"},{"key":"2023101000001321000_99.1.64.36","doi-asserted-by":"publisher","DOI":"10.2147\/TCRM.S1458"},{"key":"2023101000001321000_99.1.64.37","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.cmi.2018.04.031","article-title":"Patient-Related determinants of antibiotic use: a systematic review","volume":"25","author":"Zanichelli","year":"2019","journal-title":"Clin Microbiol Infect"}],"container-title":["Sexually Transmitted Infections"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/sextrans-2022-055518","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T03:05:13Z","timestamp":1696907113000},"score":1,"resource":{"primary":{"URL":"https:\/\/sti.bmj.com\/lookup\/doi\/10.1136\/sextrans-2022-055518"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,21]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1,17]]},"published-print":{"date-parts":[[2023,2]]}},"alternative-id":["10.1136\/sextrans-2022-055518"],"URL":"https:\/\/doi.org\/10.1136\/sextrans-2022-055518","relation":{},"ISSN":["1368-4973","1472-3263"],"issn-type":[{"value":"1368-4973","type":"print"},{"value":"1472-3263","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,21]]}}}