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Population Pharmacokinetics of Vixotrigine in Healthy Volunteers and Subjects with Trigeminal Neuralgia, Painful Lumbosacral Radiculopathy and Erythromelalgia

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background

Vixotrigine is a voltage and use dependent sodium channel blocker currently under development for treatment of various neuropathic pain indications.

Objective

The objective of this work was to develop a population pharmacokinetic model and assess effects of various covariates on pharmacokinetic parameters of vixotrigine.

Method

Plasma concentration-time data from 12 Phase 1 or 2 studies were included in the analyses. The data were obtained following administration of single or multiple doses of vixotrigine in healthy volunteers and patients. One- and two-compartment pharmacokinetic models were evaluated as base structural pharmacokinetic models. The inclusion of selected covariates was assessed using a stepwise backward elimination approach (α = 0.001) once the base/full model was developed. The predictive ability of the model was evaluated using a visual predictive check (VPC). The final model was used to evaluate effect of covariates on exposure of vixotrigine.

Results

A total of 10,263 pharmacokinetic samples collected from 465 subjects were included in the analyses. The pharmacokinetics of vixotrigine was adequately described by a two-compartment model with two transit absorption compartments and first-order elimination. Predictability of the model was also established by VPC. The final model included covariates of age, weight and carbamazepine co-administration on clearance, weight on central volume of distribution, food on absorption rate constant and formulation and Japanese race on bioavailability. None of the covariates identified had a clinically relevant effect, as impact on area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) was within ± 25%.

Conclusion

The model characterizes the pharmacokinetics of vixotrigine well, and the exposure of vixotrigine was comparable between healthy subjects and patients. None of the covariates evaluated have a clinically relevant impact on the pharmacokinetics of vixotrigine.

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Acknowledgements

These analyses and the clinical studies involved were supported by Biogen.

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Authors and Affiliations

  1. Biogen Inc., 225 Binney Street, Cambridge, MA, 02142, USA

    Himanshu Naik, Yuan Zhao, Fiona Forrestal & Simon Cleall

  2. Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA

    Howard Bockbrader & Sunny Chapel

Authors
  1. Himanshu Naik
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  2. Yuan Zhao
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  3. Fiona Forrestal
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  4. Simon Cleall
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  5. Howard Bockbrader
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  6. Sunny Chapel
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Corresponding author

Correspondence to Himanshu Naik.

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Funding

No specific funding was received for the preparation of this article.

Conflict of interest

H.N., Y.Z., S.C. (Cleall) and F.F. are employees and shareholders of Biogen. S.C. (Chapel) and H.B. are employees of Ann Arbor Pharmacometrics Group and performed the analyses funded by Biogen. The views and opinions expressed in this article are those of the authors and do not necessarily reflect the views or position of any of their employers.

Ethics approval

All the study protocol was approved by the local ethical committee.

Consent to participate

Written informed consent was obtained from each patient taking part to the study, in compliance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guideline.

Consent for publication

Not applicable.

Availability of data and material

The datasets generated during and/or analyzed from various studies are not publicly available for confidentiality reasons.

Code availability

Custom NONMEM and R codes used for model building, simulations and computation/representation of VPC are not publicly available but are available from the corresponding author upon request.

Author contributions

All authors were involved in planning, executing, data set generation, analysis interpretation and summarization of the analyses.

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Naik, H., Zhao, Y., Forrestal, F. et al. Population Pharmacokinetics of Vixotrigine in Healthy Volunteers and Subjects with Trigeminal Neuralgia, Painful Lumbosacral Radiculopathy and Erythromelalgia. Eur J Drug Metab Pharmacokinet 46, 395–404 (2021). https://doi.org/10.1007/s13318-021-00678-0

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  • DOI: https://doi.org/10.1007/s13318-021-00678-0

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