KAF156 belongs to a new class of antimalarial, the imidazolopiperazines, and is currently in clinical development for the treatment\nof uncomplicated malaria. This first-in-human, single- and multiple-ascending-dose study in 70 healthy male volunteers\ndetermined the maximum oral dose of KAF156 tolerated by healthy adults and derived pharmacokinetic data (including preliminary\nfood effect) to enable dose calculations for malaria patients. KAF156 was studied in single-dose cohorts (10 to 1,200 mg,\nincluding one 400-mg food effect cohort (4 to 10 subjects/cohort), and in multiple-dose cohorts (60 to 600 mg once daily for 3\ndays; 8 subjects/cohort). The follow-up period was 6 to 14 days after the last dose. KAF156 was tolerated, with self-limited mild\nto moderate gastrointestinal and neurological adverse events. In treated subjects after single doses, headache (n4; 11.1%),\ndiarrhea (n3; 8.3%), dizziness (n3; 8.3%), and abdominal pain (n2; 5.6%) were the most common adverse events. Headache\n(n4; 16.7%), nausea (n3; 12.5%), upper respiratory tract infection (n3; 12.5%), and dizziness (n2; 8.3%) were the\nmost common adverse events following multiple doses. KAF156 time to maximum concentration (Tmax) was between 1.0 and 6.0\nh. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased more than dose-proportionally\nin both single- and multiple-ascending-dose cohorts (terminal half-life, 42.5 to 70.7 h). There was no significant accumulation\nover 3-day repeated administration. The extent of absorption was not significantly affected by food at a single dose\nof 400 mg, while mean Cmax decreased from 778 ng/ml to 627 ng/ml and Tmax was delayed from a median of 3.0 h under fasting\nconditions to 6.0 h under fed conditions. Renal elimination is a minor route.
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