Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects.

An open-label, single-center, single-dose, parallel-group study was performed in healthy young males and females as well as healthy elderly males to examine the influence of age and gender on the pharmacokinetics of modafinil following administration of a single 200 mg oral dose. Twelve subjects were enrolled in each of the following three groups: young males, young females, and elderly males. Each fasted (overnight) subject received 2 x 100 mg modafinil tablets. Blood and urine samples were collected at various times up to 72 hours postdose for the determination of plasma and urine levels of modafinil as well as the acid and sulfone metabolites. The plasma concentrations of the individual isomers, d- and l-modafinil, were also determined. Pharmacokinetic parameters were determined by noncompartmental methods. Modafinil was well tolerated at a single oral dose of 200 mg. The most commonly reported adverse events were headache, fever, pharyngitis, and asthenia. There were no clinically meaningful differences with respect to the incidence rate of treatment-emergent adverse events among the young female, young male, and old male groups. Modafinil was rapidly absorbed after oral dosing and slowly cleared (t1/2 approximately 11-14 hr) from the body. Modafinil acid was the major urinary metabolite, which accounted for 35% to 60% of the dose. Results from this study indicated that there were age and gender effects on modafinil clearance processes. In this regard, the clearance rate of modafinil in males decreased with age while young females cleared modafinil at a faster rate than young males. Stereospecific pharmacokinetics of modafinil were also demonstrated. The d-modafinil was eliminated three times faster than the l-modafinil.

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 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.

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 treatment of excessive daytime sleepiness associated with narcolepsy. An open, 3 x 3 Latin square, randomized, cross-over study was performed in healthy males to compare the pharmacokinetics of single-dose oral modafinil (200 mg) and methylphenidate (40 mg) administered alone or in combination. Blood samples were obtained for analysis of d- and l-threo-methylphenidate and modafinil and its acid and sulfone metabolites. Pharmacokinetic parameters were determined by noncompartmental methods, but could not be evaluated for modafinil sulfone due to plasma levels that were close to the assay quantitation limit. Although sporadic differences in plasma concentrations were observed between treatments, coadministration of modafinil and methylphenidate did not significantly alter the plasma concentrations of modafinil, modafinil acid, modafinil sulfone, or methylphenidate enantiomers compared with administration of these agents alone. Half-life (t1/2), maximum concentration (Cmax), area under the concentration-time curve (AUC0-infinity), total clearance (Cl/F), and apparent volume of distribution (Vd/F) for modafinil and t1/2, Cmax, and AUC0-infinity for modafinil acid were not affected by concomitant administration of methylphenidate. Small but statistically significant increases in time to Cmax (tmax) were observed for modafinil and modafinil acid after methylphenidate coadministration compared with modafinil alone. Modafinil coadministration did not significantly alter the pharmacokinetics of d- or l-threo-methylphenidate, 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. Coadministration did not alter the extent of oral absorption and disposition of either agent. Therefore, a pharmacokinetic interaction between modafinil and methylphenidate would be unlikely.

Comparative ototoxicity of netilmicin, gentamicin, and tobramycin in cats.

Netilmicin, a semisynthetic aminoglycoside antibiotic, is less ototoxic in a variety of species than other aminoglycosides currently in therapeutic use. In this study, mixed-breed cats (four/group) were given daily sc injections of netilmicin (20, 40, and 80 mg/kg), gentamicin (20 and 40 mg/kg), or tobramycin (20, 40, and 80 mg/kg) for up to 30 weeks or until ototoxicity was observed. The animals were examined throughout the study for effects on cochlear and vestibular function. Hematologic, serum chemical, and drug-serum (24-hr postdose) assays were performed at approximate monthly intervals during the dosing period. The cochleae, kidneys, and liver were examined microscopically. The mean number of dose days required to produce vestibulotoxic effects, demonstrated by impaired righting reflex or locomotor ataxia, was from 41 to 61 in cats dosed with tobramycin (40 and 80 mg/kg) or gentamicin. No vestibular dysfunction was observed in any of the netilmicin 20-mg/kg-dosed cats, in two cats each of the tobramycin 20-mg/kg and netilmicin 40-mg/kg groups, and in one netilmicin 80-mg/kg-dosed animal. Histologic examination of the cochleae revealed degeneration of the hair cells and supporting sensory structures in the majority of cats dosed with gentamicin at 20 and 40 mg/kg and tobramycin at 40 and 80 mg/kg. Less than 50% of the tissues from cats of the tobramycin 20-mg/kg and netilmicin 40- and 80-mg/kg-dosed groups had similar degenerative cochlear changes. No cochlear damage was noted in any of the cats given netilmicin at 20 mg/kg. Results of the clinical laboratory determinations were generally unremarkable. Proximal tubular degeneration was the principal finding observed in the kidneys of the animals. Under the conditions of this study, at least a twofold (vestibular) to fourfold (cochlear) relative safety margin for ototoxicity was established in favor of netilmicin over tobramycin and gentamicin.