SINGLE-DOSE, STEADY-STATE PHARMACOKINETICS OF SERATRODAST (AA-2414) IN HEALTHY MALE AND FEMALE VOLUNTEERS

The primary objectives of this randomised, placebo-controlled, double- blind, parallel-group study were to evaluate the tolerability and phar macokinetic characteristics of repetitive, oral, total daily doses of 160, 240 or 320mg of seratrodast administered in a once-daily regimen to healthy male and female volunteers. A total of 24 volunteers (12 ma les and 12 females) received seratrodast and another 11 study particip ants received placebo. Study drug was administered once daily on study day 1 and study days 3 through 9 after overnight fasting. Blood sampl es were collected on days 1 and 9. The plasma concentrations of seratr odast increased proportionally with dose between the 160 and 240mg dos es with some evidence (mainly after single doses) of a less than propo rtional increase at the 320mg dose level. The reason for the lack of d ose proportionality could be due to saturation of the protein binding sites and/or decreased absorption at higher doses. The oral clearance and terminal half-life averaged 0.9 L/h (28% CV) and 20 hours (46% CV) , respectively, after single-dose administration. As expected from the terminal half-life, seratrodast accumulated predictably upon once-dai ly multiple administration, and steady-state was ultimately reached wi thin 7 days of administration. A gender effect was observed for peak p lasma concentrations (C-max), and area under the plasma concentration versus time curve (AUC) on day 9, with females having higher concentra tions than males. Seratrodast was found to be well tolerated after rep eated multiple doses of up to 320 mg/day.