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Systemic Exposure to Armodafinil and Its Tolerability in Healthy Elderly versus Young Men

An Open-Label, Multiple-Dose, Parallel-Group Study

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Abstract

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 (AUCτ) and maximum observed plasma drug concentration (Cmax), 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 AUCτ and Cmax values, was approximately 15% greater in elderly subjects compared with young subjects. Geometric mean ratios for AUCτ and Cmax 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 AUCτ and Cmax 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.

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Acknowledgements

This study and article were sponsored by Cephalon, Inc., Frazer, PA, USA. All authors are employees of Cephalon, Inc.

The authors wish to acknowledge Virginia Schobel, MSc (formerly of Cephalon, Inc., Frazer, PA) and Trevor Speight (Medicines Information Co., Auckland, New Zealand) for their editorial assistance, which included literature searches, editing and fact checking, graphics support and, at the request of and with guidance from the authors, support for the preparation of the outline and drafting of this manuscript. Additional editorial assistance was provided by the Curry Rockefeller Group, LLC (Tarrytown, NY). The authors would also like to acknowledge the work of the study investigators: Dr Geraldine Bichier (Center for Clinical Trials Research, Gainesville, FL) and Dr Maria Gutierrez (Comprehensive Phase One™, Miramar, FL).

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Authors and Affiliations

  1. Clinical Pharmacology Department, Cephalon, Inc., 41 Moores Road, Frazer, Pennsylvania, 19355, USA

    Mona Darwish PhD & Mary Kirby

  2. Drug Safety and Disposition Department, Cephalon, Inc., West Chester, Pennsylvania, USA

    Edward T. Hellriegel & Philmore Robertson Jr

  3. Biometrics Department, Cephalon, Inc., Frazer, Pennsylvania, USA

    Ronghua Yang

Authors
  1. Mona Darwish PhD
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  2. Mary Kirby
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  3. Edward T. Hellriegel
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  4. Ronghua Yang
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  5. Philmore Robertson Jr
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Correspondence to Mona Darwish PhD.

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Darwish, M., Kirby, M., Hellriegel, E.T. et al. Systemic Exposure to Armodafinil and Its Tolerability in Healthy Elderly versus Young Men. Drugs Aging 28, 139–150 (2011). https://doi.org/10.2165/11586370-000000000-00000

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