TOLERABILITY AND PHARMACOKINETICS OF RO42-1611 (ARTEFLENE) IN MAN

The safety, tolerability and pharmacokinetics of the antimalarial arte flene (Ro 42-1611) were evaluated in a single ascending dose, double-b lind, 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 anal yzed for unchanged drug and the 8-hydroxy-metabolite using a new HPLC assay with UV detection. Serial blood samples were also taken for phar macodynamics (ex vivo inhibition of Plasmodium falciparum growth). No serious adverse events were reported and no withdrawals occurred. Labo ratory parameters (haematology, blood chemistry, urinalysis), vital si gns blood pressure, heart rate, body temperature) and electrocardiogra ms revealed no clinically relevant changes. Highly significant inhibit ion of P. falciparum growth was observed in sera from subjects who rec eived 300 mg or higher doses as early as 30 minutes and up to 8 h post dosing. Evaluation of the pharmacokinetics from the plasma concentrat ion-time data showed that the mean C-max and AUC values increased line arly with dose up to a dose level of 1800 mg. At higher doses a platea u was reached pointing to a saturation of absorption from the gastroin testinal tract. Maximum concentrations in plasma were reached 1.7 to 3 .3 hours post-dose. The elimination half-lives were relatively short a nd ranged between 2 and 4 hours. In plasma, the 8-hydroxy-metabolite r eached approximately 3 times the C-max values of the unchanged substan ce. The T-max value and elimination half-life of the metabolite were s imilar to that of arteflene. Although this metabolite is 3-5 times les s active than the parent drug in vitro, it may contribute considerably to the antiplasmodial activity of arteflene. In urine no arteflene no r 8-hydroxy-metabolite could be detected, but other metabolites which did not appear in plasma were observed. In conclusion, arteflene was w ell tolerated up to single doses of 3600 mg p.o. Due to a subproportio nal increase in plasma concentrations above doses of 1800 mg, it is no t recommended to use higher oral doses in therapeutic studies.