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.).

FIG 1

Proposed metabolic pathways of ACT-451840 in human plasma.

FIG 2

Arithmetic mean (±SD) plasma concentration-time profile of ACT 451840 in healthy male subjects after administration of a single dose of 10, 50, 200, or 500 mg of ACT-451840 in the fasted state or 200 and 500 mg of ACT-451840 in the fed state (linear and semilogarithmic scales).

FIG 3

Arithmetic mean (±SD) plasma concentration-time profile of ACT-451840 in the food effect group (500 mg fasted and fed crossover) (linear and semilogarithmic scales).

FIG 4

Simulated concentration-time profiles for multiple once-daily doses of 200 and 500 mg of ACT-451840 in the fed state.

FIG 5

Arithmetic mean (±SD) concentration-time profiles of ACT-451840 determined by LC-MS/MS and by the bioassay for 200 mg fasted, 500 mg fasted and fed crossover, and 200 mg fed.