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Population Pharmacokinetics Analysis of Vigabatrin in Adults and Children with Epilepsy and Children with Infantile Spasms

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Abstract

Background and objectives

Vigabatrin is an inhibitor of γ-aminobutyric acid transaminase. The purpose of these analyses was to develop a population pharmacokinetics model to characterize the vigabatrin concentration–time profile for adults and children with refractory complex partial seizures (rCPS) and for children with infantile spasms (IS); to identify covariates that affect its disposition, and to enable predictions of systemic vigabatrin exposure for patients 1–12 months of age.

Methods

Vigabatrin pharmacokinetic data from six randomized controlled clinical trials and one open-label study were analyzed using nonlinear mixed-effects modeling. Data collected from 349 adults with rCPS and 119 pediatric patients with rCPS or IS were used in the analyses.

Results

A two-compartment model with first-order elimination and transit-compartment absorption consisting of five transit compartments adequately described the vigabatrin concentration–time data for these adult and pediatric patient populations. An exponential error model was used to estimate inter-individual variability for the transit-rate constant (k tr) (24.2 %), elimination rate constant (k) (14.7 %) and apparent central volume of distribution (V c/F) (18 %). For the study of children with IS, inter-occasion variability was estimated for k tr (58.1 %) and relative bioavailability (F) (26.9 %). Covariate analysis indicated that age, creatinine clearance (CLCR), and body weight were important predictors of vigabatrin pharmacokinetic parameters. Vigabatrin apparent clearance increased with increasing CLCR, consistent with renal excretion (primary pathway of vigabatrin elimination). Rate of vigabatrin absorption was dependent on age. The rate was slower in younger patients, which resulted in a smaller predicted maximum concentration and longer predicted time to maximum concentrations. Vigabatrin V c/F, apparent inter-compartmental clearance between the central and peripheral compartment, and apparent peripheral volume of distribution were increased with greater patient body weights. Sex did not contribute significantly to vigabatrin pharmacokinetic variability.

Conclusion

The model adequately described vigabatrin pharmacokinetic and enabled predictions of systemic exposures in pediatric patients 1–12 months of age.

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Acknowledgments

The authors acknowledge Susan K. Paulson, PhD, of Pharma Start, LLC, of Northbrook, IL, USA, and Michael A. Nissen, ELS, of Lundbeck LLC, Deerfield, IL, USA, for their assistance in the preparation and revision of this manuscript. This assistance was fully funded by Lundbeck.

Conflict of interest

These analyses were funded by Lundbeck LLC. Dwain Tolbert is a full-time employee of Lundbeck LLC. Mahlaqa Patel and David L. Wesche were full-time employees of Lundbeck LLC at the time this study was conducted. Aziz Karim is a Lundbeck contract employee. Jace C. Nielsen and Kenneth G. Kowalski, all of Ann Arbor Pharmacometrics Group, Inc. (Ann Arbor, Michigan USA), are paid consultants of Lundbeck LLC.

Role of funding source

These analyses were funded by Lundbeck LLC. The Ann Arbor Pharmacometrics Group authors developed the model and conducted the resulting analyses, with input and feedback from the other authors. All authors were responsible for analysis and interpretation of the data. All authors agreed upon the publication of these data, and reviewed and approved this manuscript.

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Authors and Affiliations

  1. Ann Arbor Pharmacometrics Group, Inc., 110 Miller Avenue, Garden Suite, Ann Arbor, MI, 48104, USA

    Jace C. Nielsen & Kenneth G. Kowalski

  2. Clinical Research, Lundbeck LLC, Four Parkway North, Deerfield, IL, 60015, USA

    Aziz Karim, David L. Wesche & Dwain Tolbert

  3. Regulatory Development and Registration, Lundbeck LLC, Four Parkway North, Deerfield, IL, 60015, USA

    Mahlaqa Patel

Authors
  1. Jace C. Nielsen
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  2. Kenneth G. Kowalski
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  3. Aziz Karim
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  4. Mahlaqa Patel
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  5. David L. Wesche
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  6. Dwain Tolbert
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Corresponding author

Correspondence to Jace C. Nielsen.

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Nielsen, J.C., Kowalski, K.G., Karim, A. et al. Population Pharmacokinetics Analysis of Vigabatrin in Adults and Children with Epilepsy and Children with Infantile Spasms. Clin Pharmacokinet 53, 1019–1031 (2014). https://doi.org/10.1007/s40262-014-0172-z

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  • DOI: https://doi.org/10.1007/s40262-014-0172-z

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