title: Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard.
abstract: OBJECTIVE
  To test the current U.S. Food and Drug Administration (FDA) bioequivalence standard in a comparison of generic and brand-name drug pharmacokinetic (PK) performance in "generic-brittle" patients with epilepsy under clinical use conditions.
  
  
  METHODS
  This randomized, double-blind, multiple-dose, steady-state, fully replicated bioequivalence study compared generic lamotrigine to brand-name Lamictal in "generic-brittle" patients with epilepsy (n = 34) who were already taking lamotrigine. Patients were repeatedly switched between masked Lamictal and generic lamotrigine. Intensive PK blood sampling at the end of each 2-week treatment period yielded two 12-h PK profiles for brand-name and generic forms for each patient. Steady-state area under the curve (AUC), peak plasma concentration (Cmax ), and minimum plasma concentration (Cmin ) data were subjected to conventional average bioequivalence (ABE) analysis, reference-scaled ABE analysis, and within-subject variability (WSV) comparisons. In addition, generic-versus-brand comparisons in individual patients were performed. Secondary clinical outcomes included seizure frequency and adverse events.
  
  
  RESULTS
  Generic demonstrated bioequivalence to brand. The 90% confidence intervals of the mean for steady-state AUC, Cmax , and Cmin for generic-versus-brand were 97.2-101.6%, 98.8-104.5%, and 93.4-101.0%, respectively. The WSV of generic and brand were also similar. Individual patient PK ratios for generic-versus-brand were similar but not identical, in part because brand-versus-brand profiles were not identical, even though subjects were rechallenged with the same product. Few subjects had seizure exacerbations or tolerability issues with product switching. One subject, however, reported 267 focal motor seizures, primarily on generic, although his brand and generic PK profiles were practically identical.
  
  
  CONCLUSIONS
  Some neurologists question whether bioequivalence in healthy volunteers ensures therapeutic equivalence of brand and generic antiepileptic drugs in patients with epilepsy, who may be at increased risk for problems with brand-to-generic switching. Bioequivalence results in "generic-brittle" patients with epilepsy under clinical conditions support the soundness of the FDA bioequivalence standards. Adverse events on generic were not related to the small, allowable PK differences between generic and brand.
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, Maryland, U.S.A.
authors.forename: Tricia Y
authors.initials: TY
authors.lastname: Ting
authors.affiliation: Food and Drug Administration, White Oak, Maryland, U.S.A.
authors.forename: Wenlei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Food and Drug Administration, White Oak, Maryland, U.S.A.
authors.forename: Robert
authors.initials: R
authors.lastname: Lionberger
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, U.S.A.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wong
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, U.S.A.
authors.forename: Jace W
authors.initials: JW
authors.lastname: Jones
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, U.S.A.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Kane
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, Maryland, U.S.A.
authors.forename: Allan
authors.initials: A
authors.lastname: Krumholz
authors.affiliation: Food and Drug Administration, White Oak, Maryland, U.S.A.
authors.forename: Robert
authors.initials: R
authors.lastname: Temple
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, U.S.A.
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
mesh_terms: D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016568:Drugs, Generic / Q000627:therapeutic use*; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations; D013810:Therapeutic Equivalency; D016896:Treatment Outcome; D014227:Triazines / Q000627:therapeutic use*; D014481:United States; D014486:United States Food and Drug Administration / Q000592:standards; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D016568:Drugs, Generic; D004364:Pharmaceutical Preparations; D014227:Triazines; D000077213:Lamotrigine
keywords: Bioequivalence; Generic-brittle; Lamotrigine; Narrow therapeutic index; Switchability