Assessing bioequivalence of generic modified-release antiepileptic drugs

Emily Johnson, Yi Ting Chang, Barbara Davit, Barry E. Gidal, Gregory Krauss

Research output: Contribution to journalArticle

Abstract

Objectives: The purpose of this study was to determine how closely generic modified-release antiepileptic drugs (MR-AEDs) resemble reference (brand) formulations by comparing peak concentrations (Cmax), total absorption (area under the curve [AUC]), time to Cmax (Tmax), intersubject variability, and food effects between generic and reference products. Methods: We tabulated Cmax and AUC data from the bioequivalence (BE) studies used to support the approvals of generic Food and Drug Administration-approved MR-AEDs. We compared differences in 90% confidence intervals of the generic/reference AUC and Cmax geometric mean ratios, and intersubject variability, Tmax and delivery profiles and food effects. Results: Forty-two MR-AED formulations were studied in 3,175 healthy participants without epilepsy in 97 BE studies. BE ratios for AUC and Cmax were similar between most generic and reference products: AUC ratios varied by >15% in 11.4% of BE studies; Cmax varied by >15% in 25.8% of studies. Tmax was more variable, with >30% difference in 13 studies (usually delayed in the fed compared to fasting BE studies). Generic and reference MR products had similar intersubject variability. Immediate-release AEDs showed less intersubject variability in AUC than did MR-AEDs. Conclusions: Most generic and reference MR-AEDs have similar AUC and Cmax values. Ratios for some products, however, are near acceptance limits and Tmax values may vary. Food effects are common with MR-AED products. High variability in pharmacokinetic values for once-a-day MR-AEDs suggests their major advantage compared to immediate-release AED formulations may be the convenience of less frequent dosing to improve adherence.

Original languageEnglish (US)
Pages (from-to)1597-1604
Number of pages8
JournalNeurology
Volume86
Issue number17
DOIs
StatePublished - Apr 26 2016

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Therapeutic Equivalency
Anticonvulsants
Area Under Curve
Food
Generic Drugs
Drug Compounding
United States Food and Drug Administration
Epilepsy
Fasting
Healthy Volunteers
Pharmacokinetics
Confidence Intervals

ASJC Scopus subject areas

  • Clinical Neurology

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Assessing bioequivalence of generic modified-release antiepileptic drugs. / Johnson, Emily; Chang, Yi Ting; Davit, Barbara; Gidal, Barry E.; Krauss, Gregory.

In: Neurology, Vol. 86, No. 17, 26.04.2016, p. 1597-1604.

Research output: Contribution to journalArticle

Johnson, Emily ; Chang, Yi Ting ; Davit, Barbara ; Gidal, Barry E. ; Krauss, Gregory. / Assessing bioequivalence of generic modified-release antiepileptic drugs. In: Neurology. 2016 ; Vol. 86, No. 17. pp. 1597-1604.
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