The effect of potent CYP2D6 inhibition on the pharmacokinetics and safety of deutetrabenazine in healthy volunteers.
Eur J Clin Pharmacol
; 78(1): 11-18, 2022 Jan.
Article
in En
| MEDLINE
| ID: mdl-34491372
PURPOSE: Deutetrabenazine is a deuterated form of tetrabenazine with a confirmed lower rate of CYP2D6 metabolism of the active metabolites, α- and ß-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 ß-HTBZ (2.1-fold Cmax and 5.6-fold AUC0-∞), and correspondingly, 1.6-fold Cmax and threefold AUC0-∞ for total (α + ß)-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tetrabenazine
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Paroxetine
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Vesicular Monoamine Transport Proteins
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Cytochrome P-450 CYP2D6 Inhibitors
Type of study:
Prognostic_studies
Limits:
Adult
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Female
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Humans
/
Male
Language:
En
Journal:
Eur J Clin Pharmacol
Year:
2022
Document type:
Article
Affiliation country:
Germany
Country of publication:
Germany