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

• Published in: European journal of clinical pharmacology Vol. 78; no. 1; pp. 11 - 18
• Main Authors: Schneider, F., Stamler, D., Bradbury, M. J., Loupe, P. S., Gordon, M. F., Rabinovich-Guilatt, L.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2022; Springer Nature B.V
• Subjects: Adult; Area Under Curve; Biomedical and Life Sciences; Biomedicine; Clinical Trial; CYP2D6 protein; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP2D6 Inhibitors - pharmacology; Cytochrome P450; Drug dosages; Drug interaction; Drug Interactions; Female; Half-Life; Healthy Volunteers; Humans; Male; Metabolic Clearance Rate; Metabolites; Paroxetine; Paroxetine - pharmacology; Pharmacokinetics; Pharmacology/Toxicology; Safety; Tetrabenazine; Tetrabenazine - analogs & derivatives; Tetrabenazine - pharmacokinetics; Vesicular Monoamine Transport Proteins - pharmacokinetics; Deutetrabenazine; Tetrabenazine; Deuteration; CYP2D6 inhibition
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-021-03202-0

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 C max and 1.8-fold AUC 0–∞ ) and β-HTBZ (2.1-fold C max and 5.6-fold AUC 0–∞ ), and correspondingly, 1.6-fold C max and threefold AUC 0–∞ 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.