The effect of potent CYP2D6 inhibition on the pharmacokinetics and safety of deutetrabenazine in healthy volunteers

Abstract

Purpose: Deutetrabenazine is a deuterated form of tetrabenazine with a confirmed lower rate of CYP2D6 metabolism of the active metabolites, α- and β-HTBZ. In this study, we assessed the effect of paroxetine, a potent CYP2D6 inhibitor, on the pharmacokinetics and safety of deutetrabenazine and its metabolites. Methods: In this open-label sequential drug-drug-interaction study, 24 healthy adults who were CYP2D6 extensive or intermediate metabolizers received a single deutetrabenazine 22.5-mg oral dose on days 1 and 11 and a single paroxetine 20-mg oral daily dose on days 4–12. Pharmacokinetics of deutetrabenazine and its metabolites were assessed on days 1–4 and 11–14. Paroxetine trough concentrations were obtained pre-dose on days 9–13. Safety examinations occurred throughout the study. Results: Paroxetine administered under steady-state conditions, increased exposure of the deuterated active metabolites, α-HTBZ (1.2-fold Cmax and 1.8-fold AUC0–∞) and β-HTBZ (2.1-fold Cmax and 5.6-fold AUC0–∞), and correspondingly, 1.6-fold Cmax and threefold AUC0–∞ for total (α + β)-HTBZ. Sixteen subjects reported 45 adverse events and most were mild. Headache was the most common AE reported 8 times by 7 subjects (5 following paroxetine alone; 2 following deutetrabenazine + paroxetine). Conclusions: Paroxetine-induced increases in exposure to the active deutetrabenazine metabolites were less than those previously reported for tetrabenazine, a finding expected to reduce the burden of drug interaction. In addition, single doses of 22.5 mg deutetrabenazine, when given alone or in the presence of steady-state paroxetine (20 mg daily), were safe.