Retrospective Analysis of Adverse Drug Reactions in Bioequivalence Randomized Clinical Trials

Background/Introduction: Bioequivalence studies test pharmacokinetic parameters between a reference product, whose patent has expired, vs. a test formulation containing the same active principle (AP) [1]. Although there is wide experience with these brand products in the market, it is important to m...

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Bibliographic Details
Published inDrug safety Vol. 44; no. 12; p. 1438
Main Authors Diaz-Tufinio, C, Ruiz-Aguilar, D F, Durante-Salmerón, D A, Palma-Aguirre, J A
Format Journal Article
LanguageEnglish
Published Auckland Springer Nature B.V 01.12.2021
Subjects
Adverse events
Algorithms
Aripiprazole
Bioequivalence
Clinical trials
CYP1A2 protein
CYP2D6 protein
Cytochrome P450
Neurology
Pharmacokinetics
Principles
Quetiapine
Side effects
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Summary:Background/Introduction: Bioequivalence studies test pharmacokinetic parameters between a reference product, whose patent has expired, vs. a test formulation containing the same active principle (AP) [1]. Although there is wide experience with these brand products in the market, it is important to monitor any adverse event arising from its consumption, not only in these randomized clinical trials (RCT), but throughout the real-world setting. Objective/Aim: To analyze the adverse drug reactions (ADR) derived from bioequivalence trials conducted in Mexican population, studying them by therapeutic area and metabolizing enzymes of the active principles. Methods: We analyzed retrospectively bioequivalence trials conducted between 2012 and October 2020 in the authorized third-party Axis Clinicals Latina in Mexico, with healthy volunteers. All protocols included were reviewed by an Institutional Review Board authorized by the National Commission of Bioethics (CONBIOETICA) [2], then submitted to the sanitary federal agency COFEPRIS for its approval, based on the current regulation [3], and uploaded to the National Registry of Clinical Trials [4]. The evaluation of ADR was performed through standardized algorithms, such as Naranjo algorithm, for assessing its severity, seriousness, and causality. Results: Among 246 clinical trials with 290 individual analyses, 130 unique active principles (AP) comprising 13 therapeutic areas were studied. Out of 10,602 intention-to-treat volunteers, 10,125 completed the trials without any medical condition. Overall, 4285 ADR were registered, counting 2153 for the test products and 2085 for the reference formulations (47 ADR experienced prior to any drug administration). Regarding its seriousness, all ADR were non serious (level 1 of 2); about its severity, 73.5% resulted as moderate (level 2 of 3) and only 1.0% as severe (level 3 of 3). Ranked by ADR rate (Number of ADR / subjects in each study), three AP showed a rate greater than 2 (Aripiprazole, Quetiapine and Mirtazapine), meaning several ADR experienced per subject. Then, 10 AP exhibited an ADR rate between 1-2. Four of them had rates between 0.8-1. Based on this ADR rate ranking, the top 5 of these 17 AP, as well as 13 out of these 17, belong to the neurology area, most of them being metabolized mainly by CYP2D6, CYP1A2 and CYP3A4. Conclusion: With this work, we provide a cumulative descriptive analysis of the ADR in bioequivalence experiences, reporting the AP and its therapeutic areas with which greater rates of ADR are expected. The authors aim to boost the investigation of safety data in bioequivalence RCT.
ISSN:0114-5916
1179-1942