Do regulatory bioequivalence requirements adequately reflect the therapeutic equivalence of modified-release drug products?
OBJECTIVE
To demonstrate that current regulatory requirements for bioequivalence (BE) do not always reflect therapeutic equivalence. To investigate the potential usefulness of an additional metric, the partial AUC.


METHODS
Pharmacokinetic information was reviewed and evaluated on the pharmacokinetics of modified-release methylphenidate and nifedipine products.


RESULTS
In studies of modified-release products of methylphenidate as well as of nifedipine, traditional regulatory criteria found two formulations to be bioequivalent even though their concentration profiles strongly diverged during the period of absorption. An additional metric, partial AUC, discriminated strongly between the concentrations of the drug products.


CONCLUSIONS
The current regulatory criteria for the acceptance of BE do not always reflect the therapeutic equivalence of modified-release drug products. With some modified-release products, the application of an additional metric, the partial AUC, yields an improved discriminatory representation.
Endrenyi
Laszlo
L
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. l.endrenyi@utoronto.ca
Tothfalusi
Laszlo
L
D019540:Area Under Curve; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D004335:Drug and Narcotic Control; D006801:Humans; D008774:Methylphenidate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009543:Nifedipine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency
D002121:Calcium Channel Blockers; D000697:Central Nervous System Stimulants; D003692:Delayed-Action Preparations; D008774:Methylphenidate; D009543:Nifedipine