title: Evaluation of the potential for pharmacokinetic drug-drug interaction between armodafinil and carbamazepine in healthy adults.
abstract: OBJECTIVE
  Polypharmacy is common in psychiatry practice and can lead to an increased risk of drug interactions. Armodafinil, a wakefulness-promoting agent, has been studied as adjunctive therapy for the treatment of major depressive episodes associated with bipolar I disorder. Armodafinil and the mood stabilizer carbamazepine are both inducers of and substrates for cytochrome P450 (CYP3A4). This study was designed to evaluate the bidirectional carbamazepine-armodafinil pharmacokinetic drug-drug interaction.
  
  
  METHODS
  This was an open-label, single-center study conducted in healthy adult men. Subjects assigned to group 1 received a dose of carbamazepine (200 mg) alone and a dose after pretreatment with daily dosing of armodafinil (titrated to 250 mg/d). Subjects assigned to group 2 received a dose of armodafinil (250 mg) alone and a dose after pretreatment with carbamazepine BID (titrated to 400 mg/d). Pharmacokinetic parameters for carbamazepine, armodafinil, and their major circulating metabolites were determined when dosed alone and after pretreatment with the other drug. The safety and tolerability of armodafinil and carbamazepine were also assessed throughout the study.
  
  
  RESULTS
  Eighty-one subjects enrolled in the study (group 1 = 40; group 2 = 41), of whom 79 (group 1 = 40; group 2 = 39) were evaluable for pharmacokinetic analysis and 80 (group 1 = 40; group 2 = 40) were evaluable for safety analysis. In group 1, pretreatment with armodafinil reduced systemic exposure to carbamazepine by 12% for Cmax and 25% for AUC (based on comparison of geometric means). Similarly, in group 2, pretreatment with carbamazepine reduced systemic exposure to armodafinil by 11% for Cmax and 37% for AUC. Systemic exposure to the metabolites of these agents that are formed via CYP3A4 were increased after pretreatment in each group. There were no new or unexpected adverse events.
  
  
  CONCLUSIONS
  Systemic exposure to both carbamazepine and armodafinil was reduced after pretreatment with the other drug; systemic exposure to the metabolites of each drug, which are formed via CYP3A4, was increased. These changes were consistent with the induction of CYP3A4. Both drugs were generally safe and well tolerated alone and in combination under the conditions studied. Dose adjustment may be required when initiating or discontinuing armodafinil and carbamazepine cotherapy.
authors.affiliation: Sci-Med Bridge, Malvern, Pennsylvania.
authors.forename: Mona
authors.initials: M
authors.lastname: Darwish
authors.affiliation: Teva Pharmaceuticals, Frazer, Pennsylvania. Electronic address: Mary.Bond@tevapharm.com.
authors.forename: Mary
authors.initials: M
authors.lastname: Bond
authors.affiliation: Teva Pharmaceuticals, Frazer, Pennsylvania.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Yang
authors.affiliation: Teva Pharmaceuticals, West Chester, Pennsylvania.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Hellriegel
authors.affiliation: Teva Pharmaceuticals, West Chester, Pennsylvania.
authors.forename: Philmore
authors.initials: P
authors.lastname: Robertson
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001714:Bipolar Disorder / Q000188:drug therapy; D002220:Carbamazepine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy; D004347:Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D014851:Wakefulness; D064690:Wakefulness-Promoting Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D001559:Benzhydryl Compounds; D064690:Wakefulness-Promoting Agents; D002220:Carbamazepine; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; D000077408:Modafinil
keywords: 11-epoxide; armodafinil; carbamazepine; carbamazepine-10; drug interaction