Abstract
Introduction: Armodafinil, a moderate inducer of cytochrome P450 (CYP) 3A4, has been studied as
adjunctive therapy to maintenance medications for major depressive episodes associated
with bipolar I disorder. We evaluated the effect of daily dosing with armodafinil
on the pharmacokinetics and safety of the CYP3A4 substrate aripiprazole, an atypical
antipsychotic used to treat bipolar I disorder.
Methods: Healthy adults received 15 mg aripiprazole alone and after armodafinil (250 mg/day)
pretreatment. Pharmacokinetic parameters were derived from plasma concentrations of
aripiprazole and its active metabolite, dehydro-aripiprazole, obtained over 16 days
after each aripiprazole administration. Steady-state pharmacokinetics of armodafinil
and its 2 circulating metabolites was assessed.
Results: Of 36 subjects enrolled, 24 were evaluable for pharmacokinetic analysis. Armodafinil
reduced systemic exposure to aripiprazole (Cmax, − 8%; AUC0–∞, −34%) and dehydro-aripiprazole, which is both formed and eliminated in part via
CYP3A4 (Cmax, − 10%; AUC0–∞, − 32%). Adverse events were generally consistent with known safety profiles of each
agent.
Discussion: Systemic exposure to aripiprazole and dehydro-aripiprazole was moderately reduced
following armodafinil pretreatment. The combination was generally well tolerated under
the conditions studied.
Key words
aripiprazole - dehydro-aripiprazole - armodafinil -
R-modafinil acid - modafinil sulfone
