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

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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 (AUC0–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 AUC0–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 AUC0–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.

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Acknowledgements

The authors would like to thank Enago (www.enago.com) and Dr. Adriana Palacios Rosas for the English language review.

Funding

No external funding was used to support the publication of this article.

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Authors and Affiliations

  1. Departamento de Ciencias Químico Biológicas, Universidad de las Américas Puebla, San Andrés Cholula, Puebla, Mexico

    Blanca L. Torres-García & Lucila I. Castro-Pastrana

  2. Departamento de Actuaría, Física y Matemáticas, Universidad de las Américas Puebla, San Andrés Cholula, Puebla, Mexico

    Sara Rodríguez-Rodríguez

  3. Laboratorios Clínicos de Puebla de Bioequivalencia, Puebla, Puebla, Mexico

    Larisa Estrada-Marín, Beatriz Cedillo-Carvallo & Alejandro Ruíz-Argüelles

  4. Laboratorios Clínicos de Puebla, Puebla, Puebla, Mexico

    Olga Guzmán-García & Alejandro Ruíz-Argüelles

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  1. Blanca L. Torres-García
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  2. Lucila I. Castro-Pastrana
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Corresponding author

Correspondence to Lucila I. Castro-Pastrana.

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Conflict of interest

Blanca L. Torres-García, Lucila I. Castro-Pastrana, Sara Rodríguez-Rodríguez, Larisa Estrada-Marín, Beatriz Cedillo-Carvallo, Olga Guzmán-García, and Alejandro Ruíz-Argüelles have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval

All BE trials whose data were analysed in this work were approved by the Research Ethics Committee and the Research Committee of our institution (Laboratorios Clínicos de Puebla, Laboratorios Clínicos de Puebla de Bioequivalencia). Both committees are endorsed by the Sanitary Authorization Commission of the Federal Commission for the Protection against Sanitary Risks (COFEPRIS) in Mexico (registration numbers 13CEI21114126 and 13CI21114070, respectively). Our Research Ethics Committee is also endorsed by the National Commission of Bioethics (registration No. CONBIOETICA 21CEI00120130605). After protocol approval, each BE study was further endorsed by COFEPRIS (all approval numbers are available upon request).

All analyses were performed according to the revised Declaration of Helsinki for biomedical research involving human subjects and the rules of Good Clinical Practice.

All BE trials were conducted according to the COFEPRIS guidelines and were related to BE Mexican Federal bylaws and regulations (Mexican Official Standard NOM-177-SSA1-2013) [17].

All AEs that were observed during the studies were registered under the clinical section of the final report of each study and were documented in safety reports that were submitted to the Mexican National Centre of Pharmacovigilance. All AE cases were evaluated and classified according to the Mexican Official Standard regarding pharmacovigilance, NOM-220 [8].

Consent to Participate

Informed consent was obtained from all individual participants included in all BE trials analysed in this study.

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Torres-García, B.L., Castro-Pastrana, L.I., Rodríguez-Rodríguez, S. et al. Gini Index-Based Maximum Concentration and Area Under the Curve Split Points for Analysing Adverse Event Occurrence in Bioequivalence Studies. Pharm Med 32, 51–66 (2018). https://doi.org/10.1007/s40290-017-0217-3

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