A comparison of the intrasubject variation in drug exposure between generic and brand-name drugs:a retrospective analysis of replicate design trials

AIM(S): To investigate whether differences in total and peak drug exposure upon generic substitution are due to differences between formulations or to intrasubject pharmacokinetic variability of the active substance. METHODS: This study was designed as a retrospective reanalysis of existing studies. Nine replicate design bioequivalence studies representing six drug classes were retrieved from Dutch regulatory authority, i.e. for alendronate, atorvastatin, cyclosporin, ebastine, exemestane, mycophenolate mofetil, and ropinirole. RESULTS: In most studies the intrasubject variability in total and peak drug exposure was comparable for the brand-name (in the range of 0.01-0.24 for AUC and 0.02-0.29 for Cmax on a log-scale) and generic drugs (0.01-0.23 for AUC and 0.08-0.33 for Cmax ), and was comparable with the intrasubject variability upon switching between those drugs (0.01-0.23 for AUC and 0.06-0.33 for Cmax ). The variance related to subject-by-formulation interaction can be considered negligible (-0.069-0.047 for AUC and -0.091-0.02 for Cmax ). CONCLUSION: In the investigated studies, the variation in total and peak exposure seen when a patient is switched from a brand-name drug to a generic drug is comparable to the variation seen following repeated administration of the brand-name drug in that patient. Only the intrasubject variability seems to play a crucial and decisive role in the variation in drug exposure seen; no additional formulation dependent variation in exposure is observed upon switching. Thus, our data support that, from a clinical pharmacological perspective, the benefit-risk of a generic drug is comparable to that of the brand-name drug for the medicines that were included in this investigation