A Double‐Blind, Placebo‐Controlled, Ascending‐Dose Evaluation of the Pharmacokinetics and Tolerability of Modafinil Tablets in Healthy Male Volunteers

Abstract

A randomized, double-blind, placebo-controlled, ascending-dose study was conducted to evaluate the pharmacokinetic and safety profiles of increasing modafinil doses (200 mg, 400 mg, 600 mg, 800 mg) administered orally over a 7-day period in normal healthy male volunteers. Eight subjects (six modafinil; 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 were obtained following administration of the day 1 and day 7 doses for characterization of pharmacokinetics, and trough samples were obtained prior to dosing on days 2 through 6 to assess the time to reach the steady state. Pharmacokinetic parameters were calculated using noncompartmental methods. Modafinil steady state was reached after three daily doses. Modafinil pharmacokinetics were dose and time independent over the range of 200 mg to 800 mg. Steady-state pharmacokinetics of modafinil were characterized by a rapid oral absorption rate, a low plasma clearance of approximately 50 mL/min, a volume of distribution of approximately 0.8 L/kg, and a long half-life of approximately 15 hr. Modafinil was primarily eliminated by metabolism. Modafinil acid was the major urinary metabolite. Stereospecific pharmacokinetics of modafinil were demonstrated. The d-modafinil enantiomer was eliminated at a threefold faster rate than 1-modafinil. Modafinil 200 mg, 400 mg, and 600 mg doses were generally well tolerated. The modafinil 800 mg dose panel was discontinued after 3 days of treatment due to the observation of increased blood pressure and pulse rate. The safety data from this study suggest that the maximum tolerable single daily oral modafinil dose, without titration, may be 600 mg.

Smoked Cocaine Self-Administration is Decreased by Modafinil

“…Modafinil modulates the activity of CNS catecholamine transporters, which are established sites through which many of cocaine-related effects are mediated, so it is possible that this feature played a role in altering cocaine self-administration. Consistent with such a mechanism, modafinil is well absorbed after oral administration and has a terminal elimination half-life of approximately 12-15 h (Wong et al, 1999), whereas the half-life for cocaine is only about 1 h. In addition, modafinil inhibits the firing of midbrain dopamine neurons, possibly through D 2 autoreceptors (Korotkova et al, 2007). Thus, in the current study, it is conceivable that modafinil dampened the ability of the sampled dose of cocaine to acutely increase catecholamine transmission, and thereby reduced the perceived potency and subsequent choice to self-administer the drug.…”

The psychostimulant modafinil facilitates water maze performance and augments synaptic potentiation in dentate gyrus

“…injection of modafinil of 150 mg/kg (Ishizuka et al, 2003) elevated neuronal responsiveness in the dentate gyrus to 175% for PS amplitude and 75% for the fEPSP slope, compared to the baseline, pre-injection period. Importantly, the time course of the observed changes is congruent with the rate of modafinil absorption (Wong et al, 1999a;Wong et al, 1999b).…”

“…The drug preparations were delivered for a total of 16 consecutive days, commencing 7 days before the first water-maze trial, and continuing until the end of the watermaze protocol. The target doses were 10 mg/kg and 64 mg/kg, which reflect concentrations of low-end effective dose and a high dose, respectively, for humans (Wong et al, 1999b). The testing on the water-maze began 7 days following the start of drug treatment.…”

“…The rats were injected with a single dose of modafinil (150 mg/kg i.p. ), 120 min prior to tetanization (timing was adjusted to allow modafinil absorption, which reaches M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 14 plasmatic peak levels 2 to 4 hours after oral administration with a half-life of 15 hours (Wong et al, 1999a;Wong et al, 1999b). Modafinil-treated animals expressed higher values of fEPSP slope after HFS, compared to controls (Fig.…”

Pharmacotherapy of Excessive Sleepiness: Focus on Armodafinil

“…33 The half-life of R-modafi nil is three times longer than that of S-modafinil (14 hours versus 3-4 hours, respectively). [34][35][36] Patients receiving chronic treatment with racemic modafi nil have threefold higher circulating levels of R-modafi nil than of S-modafi nil. 34,35 The prolonged circulation of R-modafi nil may mean that the majority of effects attributed to modafi nil are due to R-modafi nil; this hypothesis resulted in further investigation of R-modafi nil (armodafi nil) in patients with a variety of disorders.…”