{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:39:13Z","timestamp":1792093153395,"version":"4.4.0"},"reference-count":30,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T00:00:00Z","timestamp":1625788800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008897","name":"Janssen Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Given the increasing emergence of drug resistance in <jats:italic>Plasmodium<\/jats:italic>, new antimalarials are urgently required. P218 is an aminopyridine that inhibits dihydrofolate reductase being developed as a malaria chemoprotective drug. Assessing the effect of new compounds on cardiac intervals is key during early drug development to determine their cardiac safety.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This double\u2010blind, randomized, placebo\u2010controlled, parallel group study evaluated the effect of P218 on electrocardiographic parameters following oral administration of seven single\u2010ascending doses up to 1000\u2009mg in 56 healthy volunteers. Participants were randomized to treatment or placebo at a 3:1 ratio. P218 was administered in the fasted state with standardized lunch served 4\u2009hours after dosing. 12\u2010lead ECGs were recorded in triplicate at regular intervals on the test day, and at 48, 72, 120, 168, 192 and 240\u2009hours thereafter. Blood samples for pharmacokinetic evaluations were collected at similar time points. Concentration\u2010effect modelling was used to assess the effect of P218 and its metabolites on cardiac intervals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Concentration\u2013effect analysis showed that P218 does not prolong the QTcF, J\u2010Tpeak or TpTe interval at all doses tested. No significant changes in QRS or PR intervals were observed. Two\u2010sided 90% confidence intervals of subinterval effects of P218 and its metabolites were consistently below the regulatory concern threshold for all doses. Study sensitivity was confirmed by significant shortening of QTcF after a meal.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Oral administration of P218 up to 1000\u2009mg does not prolong QTcF and does not significantly change QRS or PR intervals, suggesting low risk for drug\u2010induced proarrhythmia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.14933","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T04:50:54Z","timestamp":1622609454000},"page":"128-137","source":"Crossref","is-referenced-by-count":5,"title":["Concentration\u2010QT modelling of the novel DHFR inhibitor P218 in healthy male volunteers"],"prefix":"10.1111","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0010-207X","authenticated-orcid":false,"given":"J\u04e7rg","family":"T\u00e4ubel","sequence":"first","affiliation":[{"name":"Richmond Pharmacology Ltd  London UK"},{"name":"Cardiovascular and Cell Sciences Research Institute St George's University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6316-5860","authenticated-orcid":false,"given":"Ulrike","family":"Lorch","sequence":"additional","affiliation":[{"name":"Richmond Pharmacology Ltd  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Ferber","sequence":"additional","affiliation":[{"name":"Statistik Georg Ferber GmbH  Riehen Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9552-0281","authenticated-orcid":false,"given":"Christopher S.","family":"Spencer","sequence":"additional","affiliation":[{"name":"Richmond Research Institute St George's University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Freier","sequence":"additional","affiliation":[{"name":"Richmond Research Institute St George's University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Coates","sequence":"additional","affiliation":[{"name":"Richmond Pharmacology Ltd  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"El Gaaloul","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Donini","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7972-1710","authenticated-orcid":false,"given":"Mohamed Farouk","family":"Chughlay","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Chalon","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,7,9]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"World Health Organization.World malaria report 2019.https:\/\/www.who.int\/publications\/i\/item\/9789241565721. 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