SINGLE-DOSE PHARMACOKINETICS OF MODAFINIL AND METHYLPHENIDATE GIVEN ALONE OR IN COMBINATION IN HEALTHY MALE-VOLUNTEERS

Modafinil is a novel wake-promoting agent being developed for treatmen t of excessive daytime sleepiness associated with narcolepsy. An open, 3 x 3 Latin square, randomized, cross-over study was performed in hea lthy males to compare the pharmacokinetics of single-dose oral modafin il (200 mg) and methylphenidate (40 mg) administered alone or in combi nation. Blood samples were obtained for analysis of d- and l-threo-met hylphenidate and modafinil and its acid and sulfone metabolites. Pharm acokinetic parameters were determined by noncompartmental methods, but could not be evaluated for modafinil sulfone due to plasma levels tha t were close to the assay quantitation limit. Although sporadic differ ences in plasma concentrations were observed between treatments, coadm inistration of modafinil and methylphenidate did not significantly alt er the plasma concentrations of modafinil, modafinil acid, modafinil s ulfone, or methylphenidate enantiomers compared with administration of these agents alone. Half-life (t(1/2)), maximum concentration (C-max) , area under the concentration-time curve (AUC(0-infinity)), total cle arance (Cl/F), and apparent volume of distribution (Vd/F) for modafini l and t(1/2), C-max, and AUC(0-infinity) for modafinil acid were not a ffected by concomitant administration of methylphenidate. Small but st atistically significant increases in time to C-max (t(max)) were obser ved for modafinil and modafinil acid after methylphenidate coadministr ation compared with modafinil alone. Modafinil coadministration did no t significantly alter the pharmacokinetics of d- or l-threo-methylphen idate, except for a small decrease in Vd/F of l-threo-methylphenidate. Concomitant methylphenidate may cause a delay in the oral absorption of modafinil, but this delay might not be relevant clinically. Coadmin istration did not alter the extent of oral absorption and disposition of either agent. Therefore, a pharmacokinetic interaction between moda finil and methylphenidate would be unlikely.