title: Evaluation of the potential for a pharmacokinetic drug-drug interaction between armodafinil and ziprasidone in healthy adults.
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.
  
  
  CONCLUSIONS
  Systemic exposure to ziprasidone was not affected by pretreatment with armodafinil. Both drugs were generally safe and well tolerated under the conditions studied.
authors.affiliation: Sci-Med Bridge, LLC, 1916 General Alexander Drive, Malvern, PA, 19355, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Darwish
authors.forename: Mary
authors.initials: M
authors.lastname: Bond
authors.forename: Ronghua
authors.initials: R
authors.lastname: Yang
authors.forename: Edward T
authors.initials: ET
authors.lastname: Hellriegel
authors.forename: Philmore
authors.initials: P
authors.lastname: Robertson
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D064690:Wakefulness-Promoting Agents / Q000009:adverse effects / Q000494:pharmacology; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D001559:Benzhydryl Compounds; D010879:Piperazines; D013844:Thiazoles; D064690:Wakefulness-Promoting Agents; C092292:ziprasidone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077408:Modafinil