title: Biopharmaceutic Risk Assessment of Brand and Generic Lamotrigine Tablets.
abstract: The therapeutic equivalence of generic and brand name antiepileptic drugs has been questioned by neurologists and the epilepsy community. A potential contributor to such concerns is pharmaceutical quality. The objective was to assess the biopharmaceutic risk of brand name Lamictal 100 mg tablets and generic lamotrigine 100 mg tablets from several manufacturers. Lamotrigine was characterized in terms of the Biopharmaceutics Classification System (BCS), including aqueous solubility and Caco-2 permeability. A panel of pharmaceutical quality tests was also performed on three batches of Lamictal, three batches of Teva generic, and one batch of each of four other generics: appearance, identity, assay, impurity, uniformity of dosage units, disintegration, dissolution, friability, and loss on drying. These market surveillance results indicate that all brand name and generic lamotrigine 100 mg tablets passed all tests and showed acceptable pharmaceutical quality and low biopharmaceutic risk. Lamotrigine was classified as a BCS class IIb drug, exhibiting pH-dependent aqueous solubility and dissolution. At pH 1.2 and 4.5, lamotrigine exhibited high solubility, whereas lamotrigine exhibited low solubility at pH 6.8, including non-sink dissolution. Lamotrigine showed high Caco-2 permeability. The apparent permeability (Papp) of lamotrigine was (73.7 ± 8.7) × 10(-6) cm/s in the apical-to-basolateral (AP-BL) direction and (41.4 ± 1.6) × 10(-6) cm/s in the BL-AP direction, which were higher than metoprolol's AP-BL Papp of (21.2 ± 0.9) × 10(-6) cm/s and BL-AP Papp of (34.6 ± 4.6) × 10(-6) cm/s. Overall, lamotrigine's favorable biopharmaceutics from a drug substance perspective and favorable quality characteristics from a tablet formulation perspective suggest that multisource lamotrigine tablets exhibit a low biopharmaceutic risk.
authors.affiliation: †Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, United States.
authors.forename: Soundarya
authors.initials: S
authors.lastname: Vaithianathan
authors.affiliation: †Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, United States.
authors.forename: Siddarth
authors.initials: S
authors.lastname: Raman
authors.affiliation: ‡Food and Drug Administration, Rockville, Maryland 20852, United States.
authors.forename: Wenlei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: §Department of Neurology, University of Maryland, Baltimore, Maryland 21201, United States.
authors.forename: Tricia Y
authors.initials: TY
authors.lastname: Ting
authors.affiliation: †Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, United States.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Kane
authors.affiliation: †Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
mesh_terms: D000927:Anticonvulsants / Q000737:chemistry; D001702:Biopharmaceutics / Q000379:methods; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D006801:Humans; D000077213:Lamotrigine; D008790:Metoprolol / Q000737:chemistry; D010539:Permeability; D018570:Risk Assessment; D012995:Solubility; D013607:Tablets / Q000737:chemistry*; D013810:Therapeutic Equivalency; D014227:Triazines / Q000737:chemistry*
chemical_list: D000927:Anticonvulsants; D013607:Tablets; D014227:Triazines; D008790:Metoprolol; D000077213:Lamotrigine
keywords: Biopharmaceutics Classification System (BCS); Caco-2 permeability; bioequivalence; brand; generic; lamotrigine; quality