title: First-in-humans study of the safety, tolerability, and pharmacokinetics of ACT-451840, a new chemical entity with antimalarial activity.
abstract: Emerging resistance to antimalarial agents raises the need for new drugs. ACT-451840 is a new compound with potent activity against sensitive and resistant Plasmodium falciparum 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 ex vivo bioassay with P. falciparum. No (serious) adverse events leading to discontinuation were reported. At the highest dose level, the peak drug concentration (Cmax) 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·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 Cmax 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.).
authors.affiliation: Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Shirin
authors.initials: S
authors.lastname: Bruderer
authors.affiliation: Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Noémie
authors.initials: N
authors.lastname: Hurst
authors.affiliation: Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Ruben
authors.initials: R
authors.lastname: de Kanter
authors.affiliation: Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Miraval
authors.affiliation: Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pfeifer
authors.affiliation: Eurofins Optimed, Gières, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Donazzolo
authors.affiliation: Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland jasper.dingemanse@actelion.com.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000178:Acrylamides / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004562:Electrocardiography; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C000619473:ACT-451840; D000178:Acrylamides; D000962:Antimalarials; D010879:Piperazines