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



Few publications focus on adverse events (AEs) or suspected adverse drug reactions (SADRs) registered during bioequivalence (BE) studies.


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.


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.


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.


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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  1. 1.

    Hershman DL, Tsui J, Meyer J, et al. The change from brand-name to generic aromatase inhibitors and hormone therapy adherence for early-stage breast cancer. J Natl Cancer Inst. 2014;106:dju319.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Kaló Z, Holtorf AP, Alfonso-Cristancho R, Shen J, Ágh T, Inotai A, Brixner D. Need for multicriteria evaluation of generic drug policies. Value Health. 2015;18:346–51.

    Article  PubMed  Google Scholar 

  3. 3.

    Seale & Associates. Update on the pharmaceutical markets in Mexico. Business insights. Mexico City; 2016. 9p. Accessed 22 Jul 2017.

  4. 4.

    Davit B, Braddy AC, Conner DP, Yu LX. International guidelines for bioequivalence of systemically available orally administered generic drug products: a survey of similarities and differences. AAPS J. 2013;15:974–90.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Lineberry N, Berlin JA, Mansi B, Glasser S, Berkwits M, Klem C, Bhattacharya A, Citrome L, et al. Recommendations to improve adverse event reporting in clinical trial publications: a joint pharmaceutical industry/journal editor perspective. BMJ. 2016;355:i5078.

    Article  PubMed  Google Scholar 

  6. 6.

    Endrenyi L, Blume HH, Tothfalusi L. The two main goals of bioequivalence studies. AAPS J. 2017;19:885–90.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Rayavarapu S, Braithwaite E, Dorsam R, Osterhout J, Furlong LA, Shetty D, Peters JR. Comparative risk assessment of formulation changes in generic drug products: a pharmacology/toxicology perspective. Toxicol Sci. 2015;146:2–10.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Secretaría de Salud. NOM-220-SSA1-2012, instalación y operación de la farmacovigilancia. Estados Unidos Mexicanos: Secretaría de Salud. Enero de 2013. Diario Oficial de la Federación; 2013.

  9. 9.

    Secretaría de Salud. NOM-220-SSA1-2016, instalación y operación de la farmacovigilancia. Estados Unidos Mexicanos: Secretaría de Salud. Julio de 2017. Diario Oficial de la Federación; 2017.

  10. 10.

    Food and Drug Administration (20993). Guidance for industry and investigators. Safety reporting requirements for INDs and BA/BE studies. Maryland: Silver Spring; 2012. p. 32.

    Google Scholar 

  11. 11.

    Galleli L, Palleria C, De Vuono A, Mumoli L, Vasapollo P, Piro B, Russo E. Safety and efficacy of generic drugs with respect to brand formulation. J Pharmacol Pharmacother. 2013;4:S110–4.

    Article  Google Scholar 

  12. 12. U.S. National Institutes of Health. Bethesda, MD: U.S. National Library of Medicine; 2017. Accessed 22 Jul 2017.

  13. 13.

    Secretaría de Salud. Registro Nacional de Ensayos Clínicos (RNEC). México: COFEPRIS. Accessed 22 Jul 2017.

  14. 14.

    Viergever RF, Li K. Trends in global clinical trial registration: an analysis of numbers of registered clinical trials in different parts of the world from 2004 to 2013. BMJ Open. 2015;5:e008932.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Wang Y, Li LX, Wang ZC, Wang YH. Evaluate multiple adverse events in crossover design bioequivalence clinical trials. Acta Pharmacol Sin. 2001;22:187–92.

    PubMed  Google Scholar 

  16. 16.

    Gurer Ç, Çakmak Pehlivanli A, Çakmak Demircigil G. Pooled bioequivalence study database from Turkey: characterisation of adverse events and determination of split points based on Gini index as a promising method. Springerplus. 2016;5:709.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Secretaria de Salud. Norma Oficial Mexicana NOM-177-SSA1-2013, que establece las pruebas y procedimientos para demostrar que un medicamento es intercambiable. Requisitos a que deben sujetarse los Terceros Autorizados que realicen las pruebas de intercambiabilidad. Requisitos para realizar los estudios de biocomparabilidad. Requisitos a que deben sujetarse los Terceros Autorizados, Centros de Investigación o Instituciones Hospitalarias que realicen las pruebas de biocomparabilidad. Estados Unidos Mexicanos: Secretaría de Salud. Septiembre de 2013. Diario Oficial de la Federación; 2013.

  18. 18.

    Investopedia, LLC. Gini index. Oaklanda, CA: Investopedia; 2017. Accessed 22 Jul 2017.

  19. 19.

    Lora E, Prada S. Técnicas de Medición Económica, Metodología y Aplicaciones en Colombia [en línea]. Quinta Edición. Cali, Colombia: Universidad ICESI; 2016. p. 5. Accessed 22 Jul 2017.

  20. 20.

    Radice A. Use of the Lorenz curve to quantify statistical nonuniformity of sediment transport rate. J Hydraul Eng. 2009;135:320–6.

    Article  Google Scholar 

  21. 21.

    Graczyk PP. Gini coefficient: a new way to express selectivity of kinase inhibitors against a family of kinases. J Med Chem. 2007;50(23):5773–9.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Schulz M, Iwersen-Bergmann S, Andresen H, Schmoldt A. Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics. Crit Care. 2012;16:R136.

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Cathcart S, Petkov J, Winefield AH, Lushington K, Rolan P. Central mechanisms of stress-induced headache. Cephalalgia. 2010;30:285–95.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Palacios-Ceña M, Fernández-Muñoz JJ, Castaldo M, Wang K, Guerrero-Peral Á, Arendt-Nielsen L, Fernández-de-Las-Peñas C. The association of headache frequency with pain interference and the burden of disease is mediated by depression and sleep quality, but not anxiety, in chronic tension type headache. J Headache Pain. 2017;18:19.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Lee HS, Noh CK, Lee KJ. The effect of acute stress on oesophageal motility and gastroesophageal reflux in healthy humans. J Neurogastroenterol Motil. 2017;23:72–9.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Mönnikes H, Tebbe JJ, Hildebrandt M, Arck P, Osmanoglou E, Rose M, Klapp B, Wiedenmann B, Heymann-Mönnikes I. Role of stress in functional gastrointestinal disorders. Evidence for stress-induced alterations in gastrointestinal motility and sensitivity. Dig Dis. 2001;19:201–11.

    Article  PubMed  Google Scholar 

  27. 27.

    Dauvilliers Y, Lopez R, Ohayon M, Bayard S. Hypersomnia and depressive symptoms: methodological and clinical aspects. BMC Med. 2013;11:78.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Pagel JF. Excessive daytime sleepiness. Am Fam Phys. 2009;79:391–6.

    CAS  Google Scholar 

  29. 29.

    European Medicines Agency. Guideline on the investigation of bioequivalence. London: Committee for medicinal products for human use; 2010. p. 27.

    Google Scholar 

  30. 30.

    Garcés-Eisele J, Ruíz-Argüelles A, Estrada-Marín L, Reyes-Núñez V, Vázquez-Pérez R, Guzmán-García O, Coutiño-Medina R, Acosta-Sandria L, Cedillo-Carvallo B. Pharmacogenetic selection of volunteers increases stringency of bioequivalence studies; the case of clopidogrel. Indian J Pharm Sci. 2014;76:281–6.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Tsang YC, Pop R, Gordon P, Hems J, Spino M. High variability in drug pharmacokinetics complicates determination of bioequivalence: experience with verapamil. Pharm Res. 1996;13:846–50.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Sweetman SC (ed). Martindale: The complete drug reference. [online] London: Pharmaceutical Press; 2017. Accessed 22 Jul 2017.

  33. 33. [Internet]. Verapamil information from; c2000-17 [Updated: 2017 July 05]. Accessed 22 Jul 2017.

  34. 34.

    Haeri A, Javadian B, Saadati R, Dadashzadeh S. Metabolite parameters as an appropriate alternative approach for assessment of bioequivalence of two verapamil formulations. Iran J Pharm Res. 2014;13:383–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Estrada-Marín L, Cedillo-Carvallo B, Herrera-Coca A, Bravo-Barragán G, Guzmán-García O, Ruíz-Argüelles A. Bioequivalence of two oral tablet formulations of betahistine 24 mg: single-dose, open-label, randomized, two-period crossover comparison in healthy individuals. J Bioequiv Availab. 2015;7:001–4.

    Google Scholar 

  36. 36.

    González-Vacarezza N, Abad-Santos F, Carcas-Sansuan A, Dorado P, Penas-Lledo E, Estévez-Carrizo F, Llerena A. Use of pharmacogenetics in bioequivalence studies to reduce sample size: an example with mirtazapine and CYP2D6. Pharmacogenom J. 2013;13:452–5.

    Article  Google Scholar 

  37. 37. Drugs A-Z; c2000-2017. Accessed 10 Nov 2017.

  38. 38.

    Law V, Knox C, Djoumbou Y, Jewison T, Guo AC, Liu Y, Maciejewski A, Arndt D, Wilson M, Neveu V, Tang A, Gabriel G, Ly C, Adamjee S, Dame ZT, Han B, Zhou Y, Wishart DS. DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res. 2014;42(1):D1091–7.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Laika B, Leucht S, Heres S, Schneider H, Steimer W. Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome. Pharmacogenom J. 2010;10(1):20–9.

    CAS  Article  Google Scholar 

  40. 40.

    Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 2012; 92(4): 414–417. Accessed 10 Nov 2017.

  41. 41.

    Lemmer B. Chronopharmacokinetics: implications for drug treatment. J Pharm Pharmacol. 1999;51(8):887–90.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Calabrese EJ. Hormesis is central to toxicology, pharmacology and risk assessment. Hum Exp Toxicol. 2010;29(4):249–61.

    Article  PubMed  Google Scholar 

  43. 43.

    Stark M. Neurotransmitters, pharmacologic synergy, and clinical strategies. Psychiatric Times. 2006. Accessed 10 Nov 2017.

  44. 44.

    Stark M. Hormesis, adaptation, and the sandpile model. Crit Rev Toxicol. 2008;38(7):641–4.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Dueñas-Laita A, Pineda F, Armentia A. Hypersensitivity to generic drugs with soybean oil. N Engl J Med. 2009;361:1317–8.

    Article  PubMed  Google Scholar 

  46. 46.

    Garrido-Siles M, Arenas-Villafranca JJ, Pérez-Ruiz E, de Linares Fernández MF, Tortajada B, Rivas-Ruiz F, Faus V, Rueda A. New cutaneous toxicities with generic docetaxel: are the excipients guilty? Support Care Cancer. 2015;23:1917–23.

    Article  PubMed  Google Scholar 

  47. 47.

    Baumann P, Hiemke C, Ulrich S, Eckeermann G, Gartner I, Gerlach M, et al. The AGNP-TDM Expert Group Consensus Guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry. 2004;37:243–65.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Timmers L, Boons CCLM, Mangnus D, Moes JE, Swart EL, Boven E, Smit EF, Hugtenburg JG. The use of erlotinib in daily practice: a study on adherence and patients’ experiences. BMC Cancer. 2011;11:284.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Singulair (montelukast sodium) [labeling-package insert]. Whitehouse Station, NJ: Merck & CO., Inc. 2016. Accessed 22 Jul 2017.

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


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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).

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