Systemic Exposure to Armodafinil and Its Tolerability in Healthy Elderly versus Young Men: An Open-Label, Multiple-Dose, Parallel-Group Study

• Published in: Drugs & aging 2011-02, Vol.28 (2), p.139-150
• Main Authors: Darwish, Mona, Kirby, Mary, Hellriegel, Edward T., Yang, Ronghua, Robertson, Philmore
• Format: Article
• Language: English
• Subjects: Adult; Age Factors; Aged; Analysis; Area Under Curve; Armodafinil; Benzhydryl Compounds - administration & dosage; Benzhydryl Compounds - adverse effects; Benzhydryl Compounds - blood; Benzhydryl Compounds - pharmacokinetics; Biological and medical sciences; Care and treatment; Central Nervous System Stimulants - administration & dosage; Central Nervous System Stimulants - adverse effects; Central Nervous System Stimulants - blood; Central Nervous System Stimulants - pharmacokinetics; Complications and side effects; Dosage and administration; Drug therapy; Drugs; Geriatrics/Gerontology; Humans; Internal Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Narcolepsy; Original Research Article; Patient outcomes; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Wakefulness - drug effects
• ISSN: 1170-229X; 1179-1969
• DOI: 10.2165/11586370-000000000-00000

Background: Armodafinil (Nuvigil®, Cephalon, Inc., Frazer, PA, USA), the longer-lasting isomer of racemic modafinil, is a nonamphetamine, wakefulnesspromoting 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