Abstract
Background
Armodafinil has been studied as adjunctive therapy for major depressive episodes associated with bipolar I disorder. This open-label, single-centre, 2-period study evaluated the effect of armodafinil, a moderate inducer of cytochrome-P450 (CYP) isoenzyme CYP3A4, on the pharmacokinetics and safety of ziprasidone, an atypical antipsychotic used to treat bipolar I disorder and metabolized in part by CYP3A4.
Methods
Thirty-five healthy subjects received ziprasidone (20 mg) alone and after armodafinil pretreatment (titrated to 250 mg/day); of those, 25 were evaluable for pharmacokinetics. Pharmacokinetic parameters were derived from plasma concentrations of ziprasidone collected prior to and over the 48 h after each ziprasidone administration. Plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone, were also obtained after repeated daily dosing of armodafinil alone. Safety and tolerability were assessed.
Results
Systemic exposure to ziprasidone was similar following administration alone or after pretreatment with armodafinil, as assessed by mean peak plasma concentration (C max, 52.1 vs 50.4 ng/mL) and area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞, 544.6 vs 469.1 ng·h/mL). Geometric mean ratios of systemic exposure (ziprasidone alone: ziprasidone after pretreatment with armodafinil) were close to unity, with associated 90 % confidence intervals (CIs) within the range of 0.80–1.25 (C max, 0.97; 90 % CI, 0.87–1.08; AUC0–∞, 0.86; 90 % CI, 0.82–0.91). Adverse events were consistent with the known safety profiles of each agent.
Conclusion
Systemic exposure to ziprasidone was not affected by pretreatment with armodafinil. Both drugs were generally safe and well tolerated under the conditions studied.
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Acknowledgments
The authors thank Gregory A. Kopia PhD, Sarah Mizne PharmD and Joyce Willetts PhD of MedVal Scientific Information Services, LLC, for providing medical writing and editorial assistance. The authors also thank Steven Gorman, who oversaw the bioanalytical work, and Cathye Shu, a former Teva employee, for useful discussions of the results. This manuscript was prepared according to the International Society for Medical Publication Professionals’ ‘Good Publication Practice for Communicating Company-Sponsored Medical Research: the GPP2 Guidelines’.
Declaration of Funding
Funding to support this study and the preparation of this manuscript was provided by Teva Pharmaceuticals, Inc.
Declaration of Financial/Other Relationships
All authors are employees or former employees of Teva Pharmaceuticals, Inc. Edward T. Hellriegel and Philmore Robertson each own stock/stock options in Teva Pharmaceuticals, Inc.
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All authors contributed to this manuscript and had full control of all primary data. The authors agree to allow the journal to review their data if requested.
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Darwish, M., Bond, M., Yang, R. et al. Evaluation of the Potential for a Pharmacokinetic Drug–Drug Interaction Between Armodafinil and Ziprasidone in Healthy Adults. Clin Drug Investig 34, 691–699 (2014). https://doi.org/10.1007/s40261-014-0220-3
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DOI: https://doi.org/10.1007/s40261-014-0220-3