PHILADELPHIA—Among patients with epilepsy, a branded version of lamotrigine is bioequivalent to the two most disparate generic lamotrigine products, according to trial results presented at the 69th Annual Meeting of the American Epilepsy Society. In addition, no patients in the Equivalence Among Generic AEDs (EQUIGEN) single-dose study were outliers with differential pharmacokinetic reactions to any of the products studied, researchers said.
Anecdotal reports of patients experiencing breakthrough seizures after switching versions of antiepileptic drugs (AEDs) raised the question of whether bioequivalence testing performed in healthy subjects for the FDA translated to similar bioequivalence in patients with epilepsy in real-world conditions.
To investigate this question, Michel Berg, MD, Professor of Neurology at the University of Rochester, and colleagues conducted a prospective, multicenter, masked, replicate, sequence-randomized, three-sequence, six-period, single-dose, pharmacokinetic trial in people with epilepsy on concomitant AEDs.
The investigators chose to study lamotrigine because of MedWatch reports of possible problems with substitution, the drug’s pharmacokinetic characteristics, and the large number of patients taking the drug. The researchers studied Lamictal and the two most disparate generic products based on in vitro dissolution and content testing, as well as data that manufacturers submitted to the FDA.
Subjects were taking at least one AED. Patients taking lamotrigine, valproate, estrogens, or sertraline were excluded.
Statistical analyses followed FDA methods for average bioequivalence (ABE), scaled ABE, and individual bioequivalence (IBE). Outlier analysis also was performed.
Of the 48 subjects randomized to treatment, 45 completed all six periods. Three subjects who completed only three periods were included in the average bioequivalence analysis, but not the variability analyses. Three serious adverse events were judged to be unrelated to the study.
All three products had similar concentration-time curves. Both generic products met bioequivalence criteria for area under curve (AUC) and maximum dose (Cmax), compared with the brand product. Replicate testing revealed no significant difference in within-subject variability.
The EQUIGEN single-dose study “demonstrated bioequivalence among brand and the two most disparate commercially available generic lamotrigine products,” the researchers concluded. Chronic-dose study results that were presented last year also demonstrated bioequivalence among lamotrigine products.
“Thinking about lamotrigine as a model agent, it looks like the FDA regulations result in drugs that are truly bioequivalent,” Dr. Berg said. “There should be an improved confidence that the FDA’s rules and regulations regarding their approval process for generic medications are sound and that people can be changed and interchanged between generics and brand with reasonable confidence that these are equivalent products.”