Simulation of the AUC Changes after Generic Substitution in Patients

To address the debate on the safety of generic substitution quantitatively, the author compared the change in AUC in virtual patients who were simulated for several different scenarios of generic substitution. In four scenarios of original (branded) to generic and generic to generic substitution, 5,000 virtual patients were simulated per scenario using the programming software R. The mean population AUC of generics ranged from 90-110% (scenarios A and B) and 80-123.5% (scenarios C and D) of the AUC of the original. Those patients who had an AUC change (ratio) as a result of drug substitution of less than 0.67 or greater than 1.5 were considered to be in potential danger due to the substitution. We found that less than 6% of patients fell outside of the cutoff range of 0.67-1.5 as a result of original to generic substitution. However, in the case of generic to generic substitution, the proportion was as high as 9-12%. This alerts us to the potential danger of generic substitution, especially for drugs with narrow therapeutic indices.