Modafinil: Expanded Options for the Treatment of Excessive Sleepiness

For reprint orders, please contact: [email protected] DRUG EVALUATION Modafinil: expanded options for the treatment of excessive sleepiness Jonathan RL Schwartz Modafinil is an oral wake-promoting agent, initially approved in December 1998 for the Integris Sleep Disorders treatment of excessive sleepiness associated with narcolepsy. Based on the results of Center of Oklahoma, Integris Southwest and additional randomized, placebo-controlled studies, the indication for modafinil was Baptist Medical Centers, expanded in January 2004 to include excessive sleepiness associated with obstructive sleep 4200 S. Douglas, apnea/hypopnea syndrome and shift work sleep disorder. Modafinil represents a safer Suite 313, Oklahoma City, OK 73109, USA alternative to CNS stimulants for the treatment of excessive sleepiness and it has become Tel: +1 405 636 1111 the most widely prescribed agent for excessive sleepiness associated with narcolepsy over Fax: +1 405 636 7995 the past 5 years. This article summarizes the key studies on modafinil, outlining the unique E-mail: SchwJR@integris- health.com pharmacologic profile, efficacy and safety. Modafinil is a unique wake-promoting medica- licensing rights to modafinil were bought by US tion that is chemically and pharmacologically pharmaceutical company Cephalon Inc., which distinct from CNS stimulants such as ampheta- subsequently purchased Lafon. mine and methylphenidate. Modafinil was first The precise mechanism of action of modafinil approved by the US Food and Drug Adminis- remains unknown. It was originally believed to tration (FDA) in December 1998 for excessive exert wake-promoting effects through α1-adren- sleepiness (ES) associated with narcolepsy. Fol- ergic activity. However, preclinical research has lowing submission of a supplemental new drug not supported a role of modafinil as an α-adren- application to the FDA, this wake-promoting ergic agonist (although at least one preclinical agent was also approved in January 2004 for the study suggests that it may require an intact α1- treatment of ES associated with obstructive adrenergic system) [1]. Modafinil does not bind to sleep apnea/hypopnea syndrome (OSAHS) and receptors for norepinephrine, serotonin, γ-ami- shift work sleep disorder (SWSD) (For nobutyric acid (GABA), adenosine, histamine-3, OSAHS, modafinil is approved as an adjunct to melatonin, glutamate, or benzodiazepines [2–5]. standard treatments for the underlying obstruc- Preclinical studies demonstrate that it is not a tion) [Modafinil (PROVIGIL®) prescribing information. noradrenergic, adenosine, or dopaminergic ago- Cephalon Inc., PA, USA (2004)]. In randomized, pla- nist, and does not inhibit monoamine oxidase B, cebo-controlled studies involving more than or phosphodiesterase II through V [1]. 1400 patients, modafinil has demonstrated Studies employing markers of neuronal activa- consistent and significant efficacy for improv- tion have demonstrated only weak dopaminergic ing wakefulness in patients with ES associated activity for modafinil compared with CNS stimu- with these three disorders of sleep or wakeful- lants. In a preclinical study that used c-fos to com- ness, with a tolerability profile superior to that pare neuronal activation in cat brains following of CNS stimulants. This article reviews the pre- administration of amphetamine, methylphenidate, clinical and clinical experience with modafinil, or modafinil (1.0, 2.5 and 5.0 mg/kg, respec- including its pharmacologic profile, efficacy for tively), both of the CNS stimulants caused wide- the treatment of ES and related symptoms, spread cortical activation in areas that included the tolerability and abuse liability. nucleus accumbens – the area of the brain that is Keywords: attention, believed to mediate the rewarding effects of drugs modafinil, narcolepsy, Research on the mechanism of action of abuse. Patterns of activation with modafinil obstructive sleep apnea/hypopnea syndrome, of modafinil were more discrete, with strong c-fos labeling lim- shift work sleep disorder, Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) ited primarily to portions of the hypothalamus [6]. sleepiness, wake-promoting is an oral wake-promoting agent with a molecu- Other data have shown increased activity along lar formula of C15H15NO2S. This compound dopamine and glutamate reward circuits with was originally developed by French company CNS stimulant use, but not with modafinil use [7]. part of Laboratorie Lafon in the 1980s. It received an Modafinil has a weak affinity for dopamine official registration in France in 1992. In 1993, reuptake sites and preclinical data have shown that 10.2217/14750708.2.2.191 © 2005 Future Medicine Ltd ISSN 1475-0708 Therapy (2005) 2(2), 191–205 191 DRUG EVALUATION – Schwartz dopamine transporter knockout mice are nonre- wakefulness, and is not associated with signifi- sponsive to the wake-promoting effects of cant increases in stereotypies, heart rate, blood modafinil [8]. pressure or anxiety [11,12,14–18]. A study by Scammell and colleagues using c-fos demonstrated decreased neuronal activity in the Pharmacokinetic profile ventrolateral preoptic area (VLPO) in rats given Modafinil displays linear pharmacokinetics, with modafinil intraperitoneally, and increased neuro- peak plasma concentrations achieved 2–4 h fol- nal activity in the tuberomammillary nucleus lowing dosing. Steady-state plasma levels are (TMN) [2]. These findings are consistent with the achieved following 2 to 4 days of dosing at 200 or current understanding of mechanisms of wakeful- 400 mg/day. The elimination half-life (approxi- ness, with the VLPO serving as the hypothalamic mately 15 h) supports a once-daily dosing sched- sleep generator and the TMN, the hypothalamic ule. Metabolism is predominantly (>90%) hepatic wake generator. The activity of sleep-promoting [19,20]. Several metabolites of modafinil have been neurons in the VLPO is suppressed by norepine- recovered in urine. However, only two of these, phrine in order to promote and maintain wake- modafinil sulfone and modafinil acid, reach fulness. A recent study by Gallopin in which rat appreciable concentrations in plasma and neither brains were exposed to modafinil and norepine- appears to exert wake-promoting effects [19,20]. phrine demonstrated that modafinil may potenti- Food delays the time to peak plasma concentra- ate the sleep-inhibiting activity of norepinephrine tion of modafinil by approximately 1 h, although in the VLPO [9]. As a result, modafinil appears to it does not affect the overall bioavailability. The reinforce norepinephrine’s sleep-inhibiting effects. pharmacokinetics of modafinil are not affected by This effect on the VLPO may allow ascending race or gender. Pharmacokinetic patterns were arousing neuronal pathways, including pathways shown to be altered in studies of elderly patients, in the TMN, to remain active. No significant those with compromised renal function, and those effect was observed when modafinil was adminis- with liver failure. The elderly patients exhibited a tered with other arousal neurotransmitters, decreased clearance and a doubling of modafinil including serotonin, carbachol, dopamine and plasma levels at a dose of 300 mg/day, compared histamine [8]. In the study by Scammell, strong c- with historically matched, younger controls [19,20]. fos labeling associated with modafinil was seen in Lower dose therapy should be considered in this the anterior cingulate cortex and other cortical group. The pharmacokinetic activity of modafinil regions that facilitate wakefulness [2]. Modafinil in children is generally similar to that in adults. was also associated with increased activity of However, while the peak plasma concentration is orexin/hypocretin-containing neurons, which approximately the same between the two popula- exert excitatory effects on wake-promoting tions (after normalization for the dosage on regions of the brain, including the TMN. Increas- a mg/kg basis), the total systemic exposure (AUC) ing evidence supports the important role that to modafinil is lower in pediatric patients due to an CNS orexin deficiencies play in the pathogenesis apparent shorter half-life. Therefore, the duration of narcolepsy [2]. of wake-promoting effect of modafinil may be Studies examining sleep patterns, behavior, reduced in this population. Modafinil is indicated and vital signs in animals given modafinil or for patients over 16 years of age. CNS stimulants have shown that effects related In patients with a mean creatinine clearance to dopaminergic activity are prominent with the of 16.6 ml/min given a single dose of CNS stimulants but weak or absent with modafinil, 200 mg, the concentration of the modafinil [10–18]. In a series of studies by Edgar inactive metabolite modafinil acid was raised and colleagues that compared modafinil with approximately ninefold (the clinical relevance methamphetamine, both agents induced equiva- of this increase remains unclear). Lower-dose lent wakefulness in rats. However, methamphet- therapy should also be considered for these amine was associated with ‘rebound patients [19,20]. Initiating modafinil therapy at hypersomnia’ in the immediate hours following half the usual starting dose (i.e., 100 mg/day) is resumption of sleep. In rats given modafinil, lost specifically indicated for those with liver fail- sleep was recovered slowly, through gradual ure, based on a study of patients with cirrhosis increases in the percent of non-REM sleep over of the liver. Compared with healthy controls, the

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