{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:59:39Z","timestamp":1790488779760,"version":"4.1.0"},"reference-count":25,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2015,2,1]],"date-time":"2015-02-01T00:00:00Z","timestamp":1422748800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Emerging resistance to antimalarial agents raises the need for new drugs. ACT-451840 is a new compound with potent activity against sensitive and resistant\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Plasmodium falciparum<\/jats:named-content>\n            strains. This was a first-in-humans single-ascending-dose study to investigate the safety, tolerability, and pharmacokinetics of ACT-451840 across doses of 10, 50, 200, and 500 mg in healthy male subjects. In the 200- and 500-mg dose groups, the effect of food was investigated, and antimalarial activity was assessed using an\n            <jats:italic>ex vivo<\/jats:italic>\n            bioassay with\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. falciparum<\/jats:named-content>\n            . No (serious) adverse events leading to discontinuation were reported. At the highest dose level, the peak drug concentration (\n            <jats:italic>C<\/jats:italic>\n            <jats:sub>max<\/jats:sub>\n            ) and the area under the plasma concentration-time curve from zero to infinity of ACT-451840 under fasted conditions reached 11.9 ng\/ml and 100.6 ng \u00b7 h\/ml, respectively, and these were approximately 13-fold higher under fed conditions. Food did not affect the half-life (approximately 34 h) of the drug, while the\n            <jats:italic>C<\/jats:italic>\n            <jats:sub>max<\/jats:sub>\n            was attained 2.0 and 3.5 h postdose under fasted and fed conditions, respectively. The plasma concentrations estimated by the bioassay were approximately 4-fold higher than those measured by liquid chromatography-tandem mass spectrometry (LC-MS\/MS). Several potentially active metabolites were also identified. ACT-451840 was well tolerated across all doses. Exposure to ACT-451840 significantly increased with food. The bioassay indicated the presence of circulating active metabolites. (This study has been registered at ClinicalTrials.gov under registration no. NCT02186002.)\n          <\/jats:p>","DOI":"10.1128\/aac.04125-14","type":"journal-article","created":{"date-parts":[[2014,11,25]],"date-time":"2014-11-25T04:28:59Z","timestamp":1416889739000},"page":"935-942","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":26,"title":["First-in-Humans Study of the Safety, Tolerability, and Pharmacokinetics of ACT-451840, a New Chemical Entity with Antimalarial Activity"],"prefix":"10.1128","volume":"59","author":[{"given":"Shirin","family":"Bruderer","sequence":"first","affiliation":[{"name":"Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"No\u00e9mie","family":"Hurst","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"de Kanter","sequence":"additional","affiliation":[{"name":"Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Miraval","sequence":"additional","affiliation":[{"name":"Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Pfeifer","sequence":"additional","affiliation":[{"name":"Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Donazzolo","sequence":"additional","affiliation":[{"name":"Eurofins Optimed, Gi\u00e8res, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper","family":"Dingemanse","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"Global malaria action plan, for a malaria-free world","author":"World Health Organization (WHO)","year":"2008","unstructured":"World Health Organization (WHO). 2008. 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