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Evaluation of the Effect of Uridine Diphosphate-Glucuronosyltransferases (UGT) Inhibition by Valproic Acid on Vixotrigine Pharmacokinetics in Healthy Volunteers

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Abstract

Background and 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

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

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

Valproic acid, a uridine diphosphate-glucuronosyltransferase inhibitor, significantly increased vixotrigine systemic exposure.

Clinical Trial Registration

ClinicalTrials.gov Identifier: NCT03385525.

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Authors and Affiliations

  1. Quantitative Pharmacology, EMD Serono, 45 Middlesex Turnpike, Billerica, MA, 01821, USA

    Yuan Zhao

  2. Biogen, Cambridge, MA, USA

    Mona Kotecha & Michael Serenko

  3. Biogen, Maidenhead, UK

    Helen Finnigan

  4. Clinical Pharmacology, Sumitovant Biopharma, New York, NY, USA

    Himanshu Naik

Authors
  1. Yuan Zhao
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  2. Mona Kotecha
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  3. Helen Finnigan
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  4. Michael Serenko
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  5. Himanshu Naik
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Corresponding author

Correspondence to Yuan Zhao.

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Funding

The clinical study was funded by Biogen.

Conflict of interest

YZ, MK, HF, MS, and HN: present or prior employees of and own stock/stock options in Biogen.

Ethics approval

The trial was registered at ClinicalTrials.gov (NCT03385525) and conducted in accordance with the Declaration of Helsinki principles and Good Clinical Practice guidelines. The institutional review board of the clinical site (Covance Clinical Research Unit, Alice, TX, USA) provided approval of the protocol.

Consent to participate

All participants provided informed written consent.

Consent for publication

Not applicable.

Availability of data and material

The data that support this clinical study are available upon reasonable request.

Code availability

Not applicable.

Author contributions

YZ and HN led the study design, data interpretation, and manuscript preparation. All authors contributed to the study execution and data analysis, and reviewed and provided input on the manuscript.

Additional information

Yuan Zhao and Himanshu Maik were prior employees of Biogen, Cambridge, MA, USA.

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Zhao, Y., Kotecha, M., Finnigan, H. et al. Evaluation of the Effect of Uridine Diphosphate-Glucuronosyltransferases (UGT) Inhibition by Valproic Acid on Vixotrigine Pharmacokinetics in Healthy Volunteers. Clin Drug Investig 42, 829–837 (2022). https://doi.org/10.1007/s40261-022-01194-y

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  • DOI: https://doi.org/10.1007/s40261-022-01194-y

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