ArticleEuropean journal of clinical pharmacology2023
Within-subject pharmacokinetic variability has a strong influence on individual exposure ratios in bioequivalence studies, hence on drug formulation interchangeability.
Article in European journal of clinical pharmacology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Deep Dive into Generic Drug Applications to Seek Harmonization of Bioequivalence Criteria for Narrow Therapeutic Index Drugs.Pharmaceutical research · 2025Article
- A Proposal for Alternative FDA Bioequivalence Criteria for Narrow Therapeutic Index Drug Products to Support Future Harmonization.Pharmaceutical research · 2025Article
- Analysis on the Impact of U.S. FDA's Narrow Therapeutic Index Bioequivalence Criteria on Generic Drug Applications.The AAPS journal · 2025Article
- Breaking barriers: how generic drugs democratize mental health.Frontiers in pharmacology · 2025Article
- A Population Pharmacokinetic Model of Tocilizumab in Kidney Transplant Patients Treated for Chronic Active Antibody-Mediated Rejection: Comparison of Plasma Exposure Between Intravenous and Subcutaneous Administration Schemes.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024Article
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Authors and funding
4 authors.
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Abstract
introductionBioequivalence between a reference and a generic drug is based on the hypothesis that a ± 20% change in blood exposure (or ± 10% for drugs with narrow therapeutic index, NTI) following the generic/reference switch will not have any therapeutic consequences. However, the individual exposure ratio between generic and reference can be higher than 1.20 (or 1.10). This study aims to analyse the different parameters influencing the individual exposure ratio, hence the conditions for reference/generic interchangeability.
methodsBioequivalence studies with a double cross-over design for a virtual drug were simulated using 100 random sets of 12, 24, 48 or 100 pairs of areas under the curve (AUC), varying the generic/reference AUC geometric mean ratios between 0.80 and 1.25 and the within-subject exposure variance of the reference and the generic formulations.
resultsThe proportion of subjects with an exposure generic/reference ratio outside the ± 10% or ± 20% acceptance intervals increases when (1) the reference within-subject variance increases; (2) the ratio of the generic within-subject variance on the reference within-subject variance increases; and (3) the generic/reference mean AUC ratio diverges from 1.0. When only considering replicated administrations of the reference, the individual exposure ratio increases with the within-subject variance, yielding values outside the usually accepted individual exposure ratio range of 0.5 to 2 for drugs with narrow therapeutic index as soon as the within-subject variance standard deviation is ≥ 0.25 (equivalent to within-patient CV% > 25%).
conclusionsInterchangeability between reference and generic formulations, especially for drugs with narrow therapeutic index can only be assumed if, the within-subject variance of generic is less or equal to the within-subject variance of reference or, if this is not the case, if the distribution of the generic/generic individual exposure ratios is included within the therapeutic margins of the reference drug.
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