Chemical formula: C₁₅H₁₅NO₂S Molecular mass: 273.35 g/mol PubChem compound: 4236
Modafinil promotes wakefulness in a variety of species, including man. The precise mechanism(s) through which modafinil promotes wakefulness is unknown.
In non-clinical models, modafinil has weak to negligible interactions with receptors involved in the regulation of sleep/wake states (e.g. adenosine, benzodiazepine, dopamine, GABA, histamine, melatonin, norepinephrine, orexin, and serotonin). Modafinil also does not inhibit the activities of adenylyl cyclase, catechol-O-methyltransferase, glutamic acid decarboxylase MAO-A or B, nitric oxide synthetase, phosphodiesterases II-VI, or tyrosine hydroxylase. While modafinil is not a direct-acting dopamine receptor agonist, in vitro and in vivo data indicate that modafinil binds to the dopamine transporter and inhibits dopamine reuptake. The wake-promoting effects of modafinil are antagonised by D1/D2 receptor antagonists suggesting that it has indirect agonist activity.
Modafinil does not appear to be a direct α1-adrenoceptor agonist. However, modafinil binds to the norepinephrine transporter and inhibits norepinephrine uptake, but these interactions are weaker than those observed with the dopamine transporter. Although modafinil-induced wakefulness can be attenuated by the α1-adrenoceptor antagonist, prazosin, in other assay systems (e.g. vas deferens) responsive to α-adrenoceptor agonists, modafinil is inactive.
In non-clinical models, equal wakefulness-promoting doses of methylphenidate and amphetamine increase neuronal activation throughout the brain, whereas modafinil unlike classical psychomotor stimulants, predominantly affects brain regions implicated in regulating arousal, sleep, wake and vigilance.
In humans, modafinil restores and/or improves the level and duration of wakefulness and daytime alertness in a dose-related manner. Administration of modafinil results in electrophysiological changes indicative of increased alertness and improvements in objective measures of ability to sustain wakefulness.
Modafinil is a racemic compound, and the enantiomers have different pharmacokinetics where the elimination t½ of the R-isomer is three times that of the S-isomer in adult humans.
Modafinil is well-absorbed with peak plasma concentration reached approximately two to four hours after administration.
Food has no effect on overall modafinil bioavailability; however, absorption (tmax) may be delayed by approximately one hour if taken with food.
Distribution
Modafinil is moderately bound to plasma protein (approximately 60%), primarily to albumin, which indicates that there is a low risk of interaction with strongly bound drugs.
Modafinil is metabolised by the liver. The chief metabolite (40–50% of the dose), modafinil acid, has no pharmacological activity.
The excretion of modafinil and its metabolites is chiefly renal, with a small proportion being eliminated unchanged (<10% of the dose).
The effective elimination half-life of modafinil after multiple doses is about 15 hours.
The pharmacokinetic properties of modafinil are linear and time-independent. Systemic exposure increases in a dose proportional manner over the range of 200-600 mg.
Severe chronic renal failure (creatinine clearance up to 20 mL/min) did not significantly affect the pharmacokinetics of modafinil administered at 200 mg, but exposure to modafinil acid was increased 9-fold. There is inadequate information to determine safety and efficacy of dosing in patients with renal impairment.
In patients with cirrhosis, the oral clearance of modafinil was decreased by approximately 60%, and the steady-state concentration doubled, compared with values in healthy subjects. The dosage of modafinil should be reduced by half in patients with severe hepatic impairment.
There are limited data available on the use of modafinil in elderly patients. In view of the potential for lower clearance and increased systemic exposure, it is recommended that patients over 65 years of age commence therapy at 100 mg daily.
For patients 6 to 7 years of age, the estimated half-life is approximately 7 hours and increases with increase in age until half-life values approach those in adults (approximately 15 hours). This difference in clearance is partially offset by the younger patients' smaller size and lower weight which results in comparable exposure following administration of comparable doses. Higher concentrations of one of the circulating metabolites, modafinil sulfone, are present in children and adolescents as compared to adults.
In addition, following repeat-dose administration of modafinil to children and adolescents, a time-dependent reduction in systemic exposure, which plateaus by approximately week 6 is observed. Once steady-state is reached, the pharmacokinetic properties of modafinil do not appear to change with continued administration for up to 1 year.
Toxicology studies by single and repeated dosing have revealed no particular toxic action in animals.
Modafinil is not considered to be mutagenic or carcinogenic.
Reproductive toxicity studies conducted in rats and rabbits showed an increased incidence in skeletal variations (changes in the numbers of ribs and delayed ossification), embryo-fetal lethality (peri-implantation loss and resorptions) and some evidence of an increase in stillbirths (rats only), in the absence of maternal toxicity, at clinically relevant exposures. There was no effect on fertility and no evidence of teratogenic potential at systemic exposures equivalent to the maximum recommended human dose.
Reproduction toxicity studies revealed no effect on fertility, nor any teratogenic effect, nor any effect on viability, growth or development of the offspring.
Animal exposure to modafinil, based on actual plasma levels in the general toxicology, reproductive and carcinogenicity studies, was less than or similar to that expected in humans. This circumstance is the result of metabolic auto-induction noted in the pre-clinical studies. However, animal exposure on a mg/kg dose basis to modafinil in the general toxicology, reproductive and carcinogenicity studies was greater than the expected exposure, calculated on a similar basis, in humans.
In the rat peri-post-natal study, modafinil concentration in milk was about 11.5 times higher than in plasma.
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