The safety, tolerability and pharmacokinetics of the antimalarial arteflene (Ro 42-1611) were evaluated in a single ascending dose, double-blind, placebo-controlled trial in healthy male volunteers. Six groups of 9 volunteers (6 active and 3 placebo) received single oral doses of 100, 300, 900, 1800, 2700 and 3600 mg as a drinking suspension in the fasted state. For pharmacokinetic evaluation serial plasma and urine samples were collected up to 48 h after drug intake. Samples were analyzed for unchanged drug and the 8-hydroxy-metabolite using a new HPLC assay with UV detection. Serial blood samples were also taken for pharmacodynamics (ex vivo inhibition of Plasmodium falciparum growth). No serious adverse events were reported and no withdrawals occurred. Laboratory parameters (haematology, blood chemistry, urinalysis), vital signs (blood pressure, heart rate, body temperature) and electrocardiograms revealed no clinically relevant changes. Highly significant inhibition of P. falciparum growth was observed in sera from subjects who received 300 mg or higher doses as early as 30 minutes and up to 8 h post dosing. Evaluation of the pharmacokinetics from the plasma concentration-time data showed that the mean Cmax and AUC values increased linearly with dose up to a dose level of 1800 mg. At higher doses a plateau was reached pointing to a saturation of absorption from the gastrointestinal tract. Maximum concentrations in plasma were reached 1.7 to 3.3 hours post-dose. The elimination half-lives were relatively short and ranged between 2 and 4 hours. In plasma, the 8-hydroxy-metabolite reached approximately 3 times the Cmax values of the unchanged substance.(ABSTRACT TRUNCATED AT 250 WORDS)