title: Evaluation of potential pharmacokinetic drug-drug interaction between armodafinil and risperidone in healthy adults.
abstract: OBJECTIVE
  Patients with bipolar I disorder and schizophrenia have an increased risk of obstructive sleep apnea. The effects of armodafinil, a weak cytochrome P450 (CYP) 3A4 inducer, on pharmacokinetics and safety of risperidone, an atypical antipsychotic used to treat major psychiatric illness, were investigated.
  
  
  METHODS
  Healthy subjects received 2 mg risperidone alone and after armodafinil pretreatment (titrated to 250 mg/day). Pharmacokinetic parameters were derived from plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone (formed via CYP2D6 and CYP3A4), collected before and over 4 days after risperidone administration, and from steady-state plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone. Safety and tolerability were assessed.
  
  
  RESULTS
  Thirty-six subjects receiving study drug were evaluable for safety; 34 were evaluable for pharmacokinetics. Risperidone maximum plasma concentration (C max) decreased from mean 16.5 ng/mL when given alone to 9.2 ng/mL after armodafinil pretreatment (geometric mean ratio [90 % CI] 0.55 [0.50-0.61]); area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) decreased from 92.3 to 44.5 ng·h/mL (geometric mean ratio [90 % CI] 0.51 [0.46-0.55]). C max and AUC0-∞ for 9-hydroxyrisperidone were also reduced (geometric mean ratios [90 % CI] 0.81 [0.77-0.85] and 0.73 [0.69-0.77], respectively). Adverse events were consistent with known safety profiles.
  
  
  CONCLUSIONS
  Consistent with CYP3A4 induction, risperidone and 9-hydroxyrisperidone systemic exposure was reduced in the presence of armodafinil. Concomitant armodafinil and risperidone use may necessitate risperidone dosage adjustment, particularly when starting or stopping coadministration of the two drugs. However, any such decision should be based on patient disease state and clinical status.
authors.affiliation: Sci-Med Bridge, LLC, Malvern, PA, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Darwish
authors.affiliation: Teva Pharmaceuticals, Frazer, PA, USA. mary.bond@tevapharm.com.
authors.forename: Mary
authors.initials: M
authors.lastname: Bond
authors.affiliation: Teva Pharmaceuticals, Frazer, PA, USA.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Yang
authors.affiliation: Teva Pharmaceuticals, West Chester, PA, USA.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Hellriegel
authors.affiliation: Teva Pharmaceuticals, West Chester, PA, USA.
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 / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D000077408:Modafinil; D018967:Risperidone / Q000009:adverse effects / Q000493:pharmacokinetics*; D064690:Wakefulness-Promoting Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D001559:Benzhydryl Compounds; D064690:Wakefulness-Promoting Agents; D018967:Risperidone; D000077408:Modafinil