Gini Index-Based Maximum Concentration and Area Under the Curve Split Points for Analysing Adverse Event Occurrence in Bioequivalence Studies

摘要

Abstract Background Few publications focus on adverse events (AEs) or suspected adverse drug reactions (SADRs) registered during bioequivalence (BE) studies. Objective The aim was to characterise AEs reported in BE studies at a Mexican investigation site between the years 2011 and 2016, and to estimate occurrence using maximum plasma concentration ( C max ) and area under the plasma concentration curve from administration to last observed concentration at time t (AUC 0– t ) values, with the Gini index method. Methods Reported AEs were recorded from 61 BE studies that were conducted by Laboratorios Clínicos de Puebla de Bioequivalencia, which is a third-party laboratory certified by the Mexican health authorities to conduct BE studies. AEs were then characterised in terms of occurrence, study period, nature, type, severity, causality and outcomes. The Gini index method was then applied, after excluding AEs that were classified as not drug-related, and distributions of SADRs were quantified according to estimated C max and AUC 0– t cut-off values. Results We classified the occurrence of SADRs in 61 BE studies after calculating Gini index-based pharmacokinetic cut-off values for 42 drugs evaluated in healthy Mexicans. Although more SADRs occurred above C max and/or AUC 0– t cut-off values in most studies, some therapeutic classes (cardiovascular and respiratory systems) were associated with larger numbers of SADRs occurring below split points. Conclusions The present data confirm the safety of BE studies, but indicate the need for further assessments of inter-individual differences according to the incidence of SADRs. The Gini index method represents an easy statistical approach for analysing safety data collected from BE studies and offers a risk management strategy for new generic medicines.