title: Assessing bioequivalence of generic modified-release antiepileptic drugs.
abstract: OBJECTIVE
  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.
authors.affiliation: From the Department of Neurology (E.L.J., G.L.K.), The Johns Hopkins University School of Medicine, Baltimore, MD; Johnson & Johnson (Y.-T.C.), New Brunswick; Merck & Co., Inc. (B.D.), Kenilworth, NJ; and University of Wisconsin (B.E.G.), School of Pharmacy, Madison, WI. ejohns92@jhmi.edu.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Johnson
authors.affiliation: From the Department of Neurology (E.L.J., G.L.K.), The Johns Hopkins University School of Medicine, Baltimore, MD; Johnson & Johnson (Y.-T.C.), New Brunswick; Merck & Co., Inc. (B.D.), Kenilworth, NJ; and University of Wisconsin (B.E.G.), School of Pharmacy, Madison, WI.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chang
authors.affiliation: From the Department of Neurology (E.L.J., G.L.K.), The Johns Hopkins University School of Medicine, Baltimore, MD; Johnson & Johnson (Y.-T.C.), New Brunswick; Merck & Co., Inc. (B.D.), Kenilworth, NJ; and University of Wisconsin (B.E.G.), School of Pharmacy, Madison, WI.
authors.forename: Barbara
authors.initials: B
authors.lastname: Davit
authors.affiliation: From the Department of Neurology (E.L.J., G.L.K.), The Johns Hopkins University School of Medicine, Baltimore, MD; Johnson & Johnson (Y.-T.C.), New Brunswick; Merck & Co., Inc. (B.D.), Kenilworth, NJ; and University of Wisconsin (B.E.G.), School of Pharmacy, Madison, WI.
authors.forename: Barry E
authors.initials: BE
authors.lastname: Gidal
authors.affiliation: From the Department of Neurology (E.L.J., G.L.K.), The Johns Hopkins University School of Medicine, Baltimore, MD; Johnson & Johnson (Y.-T.C.), New Brunswick; Merck & Co., Inc. (B.D.), Kenilworth, NJ; and University of Wisconsin (B.E.G.), School of Pharmacy, Madison, WI.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Krauss
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D062313:Databases, Pharmaceutical; D003692:Delayed-Action Preparations; D016568:Drugs, Generic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D016568:Drugs, Generic