A Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union

• DOI: 10.1002/cpt.2451
• Publication Date: 2021-10-19T13:53:03Z
• Authors: Paulo Paixão; Rita Bento Guerreiro; Nuno Silva; Kevin Blake; Milton Bonelli; Jose Augusto Guim...; Alfredo Garcia Ar...; Luis Filipe Gouveia
• Keywords: Bioequivalence; Therapeutic index

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that 90% confidence interval ratio population geometric means test product compared with reference area under plasma concentration-time curve (AUC), and certain cases maximum drug concentration (Cmax ), to be included within tighter acceptance range 90.00-111.11%. As a consequence, sponsors need recruit higher number subjects demonstrate this may seen as increasing burden development generics. This "one-size-fits-all" is particularly questionable when within-subject variability moderate high. an alternative, we propose further refined statistical approach where narrowed based on NTI drug, similar one used widening standard 80.00-125.00% highly variable drugs. narrowed, only if lower than 30%, down 90.00-111.11% 13.93% or lower. Examples Medicines Agency list show considerable reduction required sample size like tacrolimus colchicine, predicted 20-30%. In these cases, less demanding without any expected increase risks, since patients treated products high are frequently exposed bioavailability differences larger 10%.