A preclinical study comparing scintigraphy imaging, pharmacokinetics and endometrial receptivity of sustained release vs conventional formulation of dydrogesterone

Purpose: Once-daily sustained release (SR) dydrogesterone 20 mg formulation is a patient complaint alternative for conventional oral dydrogesterone (10 mg) formulations, which have short half-life, fluctuating hormone levels and requiring frequent dosing. The aim of the study was to compare the pharmacokinetics and pharmacodynamics of SR versus conventional dydrogesterone using rabbit model. Methods: The scintigraphy was used to assess the in vivo SR behavior of the radiolabeled dydrogesterone formulations. Blood samples were collected at predesignated time points to determine kinetic parameters. For endometrial receptivity, animals were treated with once-daily SR dydrogesterone (2 mg) started with day of mating until end of first trimester. Ultrasonic assessment, biochemical changes, and endometrial histopathology was evaluated post-treatment. Comparison was made against conventional dydrogesterone and animals treated with saline (control). Results: Scintigraphy revealed prolonged disintegration and sustained drug release from SR dydrogesterone. The two-fold higher t _max (6 h) of SR dydrogesterone compared to conventional (3 h), confirmed the SR behavior. SR dydrogesterone (34.8±5.1 ng.h/mL) demonstrated nearly 2-fold higher AUC _0-48 compared to conventional dydrogesterone (14.4±2.8 ng.h/mL), however at same dose AUC _0-48 were comparable. ER scores of ultrasound assessment, level of progesterone-induced blocking factor (PIBF), and integrin αVβ3 was not significantly different among both the treatments, but were significantly higher (p<0.05) than control. Interestingly, level of vascular endothelial growth factor (VEGF) was statistically higher for SR dydrogesterone compared to conventional dydrogesterone (p<0.05) and control (p<0.001). In accordance, endometrium of animals treated with SR dydrogesterone showed dense vasculature compared to moderate for conventional dydrogesterone and low for control group animals. Nonetheless, both the treatments were found to be safe and no changes in endometrial glands, lining, shape and other microstructures were observed post-treatment. Conclusion: Once-daily SR dydrogesterone 20 mg is comparable to twice-daily conventional dydrogesterone 10 mg in kinetics and in enhancing endometrial receptivity during first trimester.