Pooled bioequivalence study database from Turkey: characterization of adverse events and determination of split points based on Gini Index as a promising method

Abstract

Background: Manufacturing of and medication with generic drugs is increasing around the world. Bioequivalence (BE) studies are being performed routinely by Contract Research Organisations (CROs) in Turkey. However, an overall evaluation for the attended volunteers, examined Active Pharmaceutical Ingredients (APIs) and the observed adverse events have not been studied in the field. Objective: Our aim was to revisit and compile the BE studies carried out between the years 2000-2013 of a CRO (N-CRO) in Turkey. Methods: A dataset of 261 BE studies has been created for the observed adverse events with regards to the frequency, type, and drug subgroups. As an advanced evaluation, the Gini Index method has been used in the 63 available BE studies to obtain split points for two pharmacokinetic parameters, area under the plasma/serum concentration (AUC) and maximum plasma/serum concentration (Cmax), in order to investigate their likely effect on the adverse events. Results: Thousand six hundred and forty two adverse events were found in the 261 BE studies involving 7828 volunteers with the frequency of 6.29 per study and 0.21 per volunteer. The most frequently observed adverse events were; headache, somnolence, nausea, dizziness and vomiting, respectively. Hundred and nine different APIs were observed. 'Genitourinary system and sex hormones' subgroup drugs had the highest frequency of the adverse events. Adverse event frequencies above the identified split points for Cmax and AUC values were higher than the frequencies below them. Conclusion: The review of 13 years period of BE studies revealed that the demographic properties of the volunteers and the study designs were in compliance with national and international guidelines. The promising outcome could be showing the increase of the adverse event frequencies above the obtained split points as the reflection of the likely individual pharmacokinetic differences in the adverse event occurence.