title: Systemic exposure to armodafinil and its tolerability in healthy elderly versus young men: an open-label, multiple-dose, parallel-group study.
abstract: BACKGROUND
  Armodafinil (Nuvigil(®), Cephalon, Inc., Frazer, PA, USA), the longer-lasting isomer of racemic modafinil, is a nonamphetamine, wakefulness-promoting medication. In patients with excessive sleepiness associated with shift work disorder, treated obstructive sleep apnoea, or narcolepsy, armodafinil has been found to improve wakefulness throughout the shift or day. In addition, while not approved for this indication, armodafinil has been found to improve excessive sleepiness associated with jet-lag disorder.
  
  
  OBJECTIVE
  This study evaluated systemic exposure to armodafinil and its two major circulating metabolites, R-modafinil acid and modafinil sulfone, and assessed the tolerability profile of armodafinil in elderly and young subjects.
  
  
  METHODS
  The pharmacokinetics and tolerability of armodafinil were assessed in an open-label, multiple-dose, parallel-group study in two groups (n = 25 in each group) of healthy men (elderly group aged ≥65 years and young group aged 18-45 years) who received armodafinil 50 mg on day 1, 100 mg on day 2 and 150 mg once daily on days 3 through 7. Plasma concentrations of armodafinil and its metabolites were quantified over 72 hours following the last dose on day 7. Pharmacokinetic parameters, including area under the plasma drug concentration-versus-time curve during a dosing interval (AUC(τ)) and maximum observed plasma drug concentration (C(max)), and tolerability were assessed.
  
  
  RESULTS
  All 50 subjects enrolled in the study were evaluable for tolerability and 49 were included in the pharmacokinetic analysis. One elderly subject was excluded from the pharmacokinetic analyses because of apparent noncompliance with armodafinil dosing. Systemic exposure following administration of armodafinil, as measured by steady-state AUC(τ) and C(max) values, was approximately 15% greater in elderly subjects compared with young subjects. Geometric mean ratios for AUC(τ) and C(max) in the two groups were 1.14 (95% CI 1.03, 1.25; p = 0.0086) and 1.15 (95% CI 1.08, 1.24; p = 0.0002), respectively. When data were analysed for elderly subgroups, systemic exposure in the old-elderly group (age ≥75 years; n = 7) was 27% greater than in young subjects, as compared with 10% greater in the young-elderly group (age 65-74 years; n = 17). Although steady-state exposure to the metabolite R-modafinil acid was also higher in elderly than in young subjects (geometric mean ratios for AUC(τ) and C(max) were 1.73 and 1.61, respectively; p < 0.0001), there were no significant differences in systemic exposure to modafinil sulfone. Armodafinil was generally well tolerated by both groups. Headache (four subjects in each group), nausea (one in the elderly group and four in the young group), insomnia (two in the elderly group and one in the young group), and dizziness (two in the young group) were the most common adverse events.
  
  
  CONCLUSIONS
  Systemic exposure following administration of armodafinil is increased in the elderly in comparison with younger subjects, particularly in those aged ≥75 years. Although the increase in plasma armodafinil concentration in elderly subjects does not appear to result in more adverse events compared with young subjects, consideration should be given to the use of lower dosages of armodafinil for the management of excessive sleepiness in older patients, particularly the very elderly.
authors.affiliation: Clinical Pharmacology Department, Cephalon, Inc., Frazer, Pennsylvania 19355, USA. mdarwish@cephalon.com
authors.forename: Mona
authors.initials: M
authors.lastname: Darwish
authors.forename: Mary
authors.initials: M
authors.lastname: Kirby
authors.forename: Edward T
authors.initials: ET
authors.lastname: Hellriegel
authors.forename: Ronghua
authors.initials: R
authors.lastname: Yang
authors.forename: Philmore
authors.initials: P
authors.lastname: Robertson
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D000077408:Modafinil; D014851:Wakefulness / Q000187:drug effects
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D000077408:Modafinil