Preclinical Assessment of the Impact of Quality Analytics on Pharmacokinetics and Concentrations of Dydrogesterone in Endometrial Tissue

Background and Objectives: Generic dydrogesterone products are widely indicated in various conditions such as infertility, menstrual disorders, and the prevention of miscarriage. Moreover, the therapeutic equivalence of generic dydrogesterone products has never been explored, despite reports of interindividual variability in the bioavailability of dydrogesterone. Therefore, this study aimed to compare two generic formulations of dydrogesterone (A and B) by evaluating the respective quality, pharmacokinetics, and endometrial tissue concentrations of these formulations in rats. Methods: Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and the drug content were compared in the quality analysis. Meanwhile, dissolution and rat plasma kinetic profiles were compared to determine the in vitro and in vivo equivalence. Endometrial drug levels were assessed by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and in vivo imaging. Results: The DSC and XRD results revealed that a higher percentage of the dydrogesterone in formulation A was amorphous, compared to formulation B, where the dydrogesterone was more crystalline. The difference in drug content between the formulations was not significant (p > 0.05), and the dissolution profile and plasma bioavailability of formulations A and B were similar (p > 0.05). LC-MS/MS analysis showed that dydrogesterone levels in the endometrial tissue of rats treated with formulation A were markedly higher compared to those treated with formulation B. The in vivo imaging results corroborated with the LC-MS/MS analysis, with nearly 43.0% higher dydrogesterone accumulation observed in the uterus of animals treated with formulation A compared to formulation B. Interpretation and Conclusion: These data exhibited that therapeutic inequivalence may exist between the generic formulations of dydrogesterone; hence, the generic formulation should be carefully selected.