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Clinical Pharmacokinetics

, Volume 44, Issue 5, pp 517–523 | Cite as

Lack of Pharmacokinetic Interactions Between Steady-State Zonisamide and Valproic Acid in Patients with Epilepsy

  • Isabelle Ragueneau-Majlessi
  • Rene H. Levy
  • Martin Brodie
  • David Smith
  • Jaymin Shah
  • John S. Grundy
Original Research Article

Abstract

Objectives

This study evaluated the effect of the addition of zonisamide on valproic acid (valproate sodium) pharmacokinetics under steady-state conditions in patients with epilepsy. A second aim was to characterise zonisamide pharmacokinetics in the presence of valproic acid.

Methods

Twenty-two patients (males and females, 18–55 years of age) with their seizure disorder stabilised on valproic acid monotherapy were included in a two-centre, open-label, one-way drug-interaction trial. The zonisamide dose was gradually increased from 100 mg/day to 400 mg/day. Three pharmacokinetic profiles were obtained: on days −7 and −1, to assess pharmacokinetic parameters of oral valproic acid administered alone, and on day 35, after 14 days of zonisamide treatment at the maximal tolerated dose, to evaluate the effect of zonisamide on valproic acid pharmacokinetics and to characterise zonisamide pharmacokinetics in the presence of valproic acid.

Results

Seventeen patients completed the study, with 16 patients contributing to the pharmacokinetic analyses. Coadministration of zonisamide and valproic acid appeared reasonably well tolerated. Steady-state dosing of zonisamide (200mg twice daily) had no statistically significant effect on the mean (± SD) maximum observed plasma concentration (Cmax) [70.8 ± 20.5 vs 69.2 ± 27.0 μg/mL], area under the plasma concentration-time curve from the time of dosing to 12 hours post-dose (AUC12) [689.3 ± 250.4 vs 661.8 ± 251.3 μg · h/mL] or other evaluated pharmacokinetic parameters for valproic acid measured before and after zonisamide administration. Furthermore, 90% confidence intervals for the ratio of the geometric means (day 35/day −1) of valproic acid pharmacokinetic exposure measures fell only slightly outside the ‘no effect’ range of 0.80–1.25. In the presence of valproic acid, mean zonisamide oral clearance (1.23 L/h) and elimination half-life (52.5 hours) are generally consistent with values reported for healthy volunteers receiving zonisamide monotherapy.

Conclusion

There is no apparent clinically significant effect of steady-state dosing of zonisamide on valproic acid pharmacokinetics, and valproic acid did not appear to affect the pharmacokinetics of zonisamide, indicating that no dosage adjustment of either drug should be required when they are used in combination in patients with epilepsy.

Keywords

Valproic Acid Zonisamide Valproate Sodium Felbamate Valproic Acid Concentration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This research was funded by Elan Pharmaceuticals. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Isabelle Ragueneau-Majlessi
    • 1
  • Rene H. Levy
    • 1
  • Martin Brodie
    • 2
  • David Smith
    • 3
  • Jaymin Shah
    • 4
  • John S. Grundy
    • 5
  1. 1.Department of PharmaceuticsUniversity of WashingtonSeattleUSA
  2. 2.Epilepsy UnitWestern InfirmaryGlasgowScotland
  3. 3.Clinical Trials UnitWalton Centre for Neurology and NeurosurgeryLiverpoolEngland
  4. 4.Gilead Sciences Inc.Foster CityUSA
  5. 5.Elan Pharmaceuticals Inc.San DiegoUSA

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