A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers

A randomized, double-blind, placebo-controlled ascending-dose study was con ducted to evaluate the pharmacokinetic and safety profiles of increasing mo dafinil doses (200 mg, 400 mg, 600 mg, 800 mg) administered orally over a 7 -day period in normal healthy male volunteers. Eight subjects (six modafini l; two placebo) were randomized to each of the four dose groups. Modafinil or a placebo was administered once daily for 7 days. Serial blood samples w ere obtained following administration of the day 1 and day 7 doses for char acterization of pharmacokinetics, and trough samples were obtained prior to dosing on days 2 through 6 to assess the time to reach the steady state. P harmacokinetic parameters were calculated using noncompartmental methods. M odafinil steady state was reached after three daily doses. Modafinil pharma cokinetics were dose and time independent over the range of 200 mg to 800 m g. Steady-state pharmacokinetics of modafinil were characterized by a rapid oral absorption rate, a low plasma clearance of similar to 50 mL/min, a vo lume of distribution of similar to 0.8 L/kg, and a long half-life of simila r to 15 hr. Modafinil was primarily eliminated by metabolism, Modafinil aci d was the major urinary metabolite. Stereospecific pharmacokinetics of moda finil were demonstrated. The d-modafinil enantiomer was eliminated at a thr eefold faster rate than 1-modafinil; Modafinil 200 mg, 400 mg, and 600 mg d oses were generally well tolerated. The modafinil 800 mg dose panel was dis continued after 3 days of treatment due to the observation of increased blo od pressure and pulse rate. The safety data from this study suggest that th e maximum tolerable single daily oral modafinil dose, without titration, ma y be 600 mg. Journal of Clinical Pharmacology 1999;30-40 (C) 1999 the Ameri can College of Clinical pharmacology.