Analysis of the Mechanism of Prolonged Persistence of Drug Interaction between Terbinafine and Amitriptyline or Nortriptyline

Abstract

The purpose of the study was to quantitatively estimate and predict drug interactions between terbinafine and tricyclic antidepressants (TCAs), amitriptyline or nortriptyline, based on in vitro studies. Inhibition of TCA-metabolizing activity by terbinafine was investigated using human liver microsomes. Based on the unbound K values obtained in vitro and reported pharmacokinetic parameters, a pharmacokinetic model of drug interaction was fitted to the reported plasma concentration profiles of TCAs administered concomitantly with terbinafine to obtain the drug-drug interaction parameters. Then, the model was used to predict nortriptyline plasma concentration with concomitant administration of terbinafine and changes of area under the curve (AUC) of nortriptyline after cessation of terbinafine. The CYP2D6 inhibitory potency of terbinafine was unaffected by preincubation, so the inhibition seems to be reversible. Terbinafine competitively inhibited amitriptyline or nortriptyline E-10-hydroxylation, with unbound K values of 13.7 and 12.4 nM, respectively. Observed plasma concentrations of TCAs administered concomitantly with terbinafine were successfully simulated with the drug interaction model using the in vitro parameters. Model-predicted nortriptyline plasma concentration after concomitant nortriptylene/terbinafine administration for two weeks exceeded the toxic level, and drug interaction was predicted to be prolonged; the AUC of nortriptyline was predicted to be increased by 2.5- or 2.0- and 1.5-fold at 0, 3 and 6 months after cessation of terbinafine, respectively. The developed model enables us to quantitatively predict the prolonged drug interaction between terbinafine and TCAs. The model should be helpful for clinical management of terbinafine-CYP2D6 substrate drug interactions, which are difficult to predict due to their time-dependency.

Antifungal Selection for the Treatment of Onychomycosis: Patient Considerations and Outcomes

“…87 Terbinafine may increase plasma concentrations of imipramine, desipramine, amitriptyline, nortriptyline, and paroxetine, and may induce thirst, nausea, and vertigo when taken together with these medications. 100 A case report of an older female prescribed the antipsychotic perphenazine along with terbinafine for onychomycosis developed extrapyramidal symptoms including akathisia and gait disturbances. 100,101 Terbinafine also decreases clearance of betablockers.…”

“…100 A case report of an older female prescribed the antipsychotic perphenazine along with terbinafine for onychomycosis developed extrapyramidal symptoms including akathisia and gait disturbances. 100,101 Terbinafine also decreases clearance of betablockers. A 63-year-old man on metoprolol experienced symptomatic bradycardia after beginning terbinafine 250mg for https://doi.org/10.2147/IDR.S431526…”