Analysis of the features of planning bioequivalence studies with adaptive design for drug products analogous to endogenous compounds ademetionine

Introduction. Adaptive design in clinical bioequivalence studies offers a more flexible approach, allowing for modifications to protocols during the trial based on accumulated data. This is particularly relevant for drugs that are analogs of endogenous compounds, such as ademetionine, due to the presence of endogenous concentrations, potential physiological fluctuations, and homeostatic mechanisms. Given that ademetionine is included in the clinical guidelines by the Ministry of Health of the Russian Federation for treating various liver diseases, there is significant interest in developing generic formulations, which necessitates careful planning of clinical studies.

Aim. The aim of this work is to analyze approved protocols for bioequivalence studies with adaptive designs for a drug product that is an analog of the endogenous compound ademetionine, specifically enteric-coated tablets.

Materials and methods. A search was conducted in the database of approved clinical trials by the State Register of Medicines of the Ministry of Health of the Russian Federation using keywords "adaptive design" and "bioequivalence" for the period from 2023 to 2024.

Results and discussion. The article analyzes nine bioequivalence protocols with adaptive designs related to Potvin C's methodology for drugs analogous to the endogenous compound ademetionine in enteric-coated tablet form. The primary endpoints were pharmacokinetic parameters C_max and AUC_0–t. Ademetionine was studied as the evaluated analyte. In 77.8 % of the protocols, there was a planned assessment of the endogenous background of ademetionine followed by adjustments to pharmacokinetic parameters. Sample size calculations were not performed in these protocols due to the lack of reported values for the coefficient of intra-individual variation (CV_intra) for C_max and AUC_0–t of ademetionine in literature.

Conclusion. The analysis results indicate that a well-planned bioequivalence study with an adaptive design (until CV_intra values for ademetionine are published in specialized literature) is rational for developing generic formulations of ademetionine, with an assessment of the endogenous background. Considering the modified dosage form, it is necessary to conduct bioequivalence studies with administration both fasting and after meals.

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