Evaluation of the Effect of Uridine Diphosphate-Glucuronosyltransferases (UGT) Inhibition by Valproic Acid on Vixotrigine Pharmacokinetics in Healthy Volunteers.
Journal
Clinical drug investigation
ISSN: 1179-1918
Titre abrégé: Clin Drug Investig
Pays: New Zealand
ID NLM: 9504817
Informations de publication
Date de publication:
Oct 2022
Oct 2022
Historique:
accepted:
16
08
2022
pubmed:
1
9
2022
medline:
12
10
2022
entrez:
31
8
2022
Statut:
ppublish
Résumé
Vixotrigine is a voltage-dependent and use-dependent sodium channel blocker in development for the treatment of neuropathic pain. Metabolism of vixotrigine is primarily through glucuronidation, resulting in the major M13 metabolite. Two additional major metabolites formed are M14 and M16. This study was designed to evaluate the effects of a uridine diphosphate-glucuronosyltransferase inhibitor, valproic acid, on vixotrigine pharmacokinetics. This open-label, fixed-sequence, phase I study enrolled 30 healthy volunteers who received a single dose of vixotrigine 150 mg on day 1 and day 16 following an 8-h fast. On days 8-22, volunteers received valproic acid 500 mg three times daily. A mixed-effects model was used to analyze the effect of valproic acid on the natural log-transformed pharmacokinetic parameters of vixotrigine and its metabolites including maximum concentration and area under the concentration-time curve from time zero to infinity. Vixotrigine systemic exposure (area under the concentration-time curve from time zero to infinity) was increased by approximately 70% following the addition of valproic acid with a negligible effect on maximum concentration. Valproic acid administration also impacted vixotrigine metabolites: M13 exposure decreased by approximately 50% and M13 maximum concentration decreased by approximately 70%; increased exposure was noted for the M14 (approximately 100%) and M16 (approximately 70%) metabolites. Valproic acid, a uridine diphosphate-glucuronosyltransferase inhibitor, significantly increased vixotrigine systemic exposure. ClinicalTrials.gov Identifier: NCT03385525.
Sections du résumé
BACKGROUND AND OBJECTIVE
OBJECTIVE
Vixotrigine is a voltage-dependent and use-dependent sodium channel blocker in development for the treatment of neuropathic pain. Metabolism of vixotrigine is primarily through glucuronidation, resulting in the major M13 metabolite. Two additional major metabolites formed are M14 and M16. This study was designed to evaluate the effects of a uridine diphosphate-glucuronosyltransferase inhibitor, valproic acid, on vixotrigine pharmacokinetics.
METHODS
METHODS
This open-label, fixed-sequence, phase I study enrolled 30 healthy volunteers who received a single dose of vixotrigine 150 mg on day 1 and day 16 following an 8-h fast. On days 8-22, volunteers received valproic acid 500 mg three times daily. A mixed-effects model was used to analyze the effect of valproic acid on the natural log-transformed pharmacokinetic parameters of vixotrigine and its metabolites including maximum concentration and area under the concentration-time curve from time zero to infinity.
RESULTS
RESULTS
Vixotrigine systemic exposure (area under the concentration-time curve from time zero to infinity) was increased by approximately 70% following the addition of valproic acid with a negligible effect on maximum concentration. Valproic acid administration also impacted vixotrigine metabolites: M13 exposure decreased by approximately 50% and M13 maximum concentration decreased by approximately 70%; increased exposure was noted for the M14 (approximately 100%) and M16 (approximately 70%) metabolites.
CONCLUSIONS
CONCLUSIONS
Valproic acid, a uridine diphosphate-glucuronosyltransferase inhibitor, significantly increased vixotrigine systemic exposure.
CLINICAL TRIAL REGISTRATION
BACKGROUND
ClinicalTrials.gov Identifier: NCT03385525.
Identifiants
pubmed: 36045316
doi: 10.1007/s40261-022-01194-y
pii: 10.1007/s40261-022-01194-y
doi:
Substances chimiques
Phenyl Ethers
0
Sodium Channel Blockers
0
Uridine Diphosphate
58-98-0
Valproic Acid
614OI1Z5WI
Proline
9DLQ4CIU6V
Glucuronosyltransferase
EC 2.4.1.17
vixotrigine
QQS4J85K6Y
Banques de données
ClinicalTrials.gov
['NCT03385525']
Types de publication
Clinical Trial, Phase I
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
829-837Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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