Abstract

PHARMACOKINETIC AND PHARMACODYNAMIC COMPARISON BETWEEN NOVEL SUSTAINED RELEASE VS CONVENTIONAL DYDROGESTERONE USED IN PREGNANCY WITH THE HELP OF SCINTIGRAPHY (EPSAR STUDY)

Rajvee A. Soni*, Gaurav K. Jain, Devesh Tewari, Nilesh Chandra, Nazeer Hasan

ABSTRACT

Objective: To compare the pharmacokinetics and pharmacodynamics of once-daily sustained-release (SR) dydrogesterone 20 mg with twice-daily conventional dydrogesterone 10 mg in a rabbit model. Methods: Technetium-99m scintigraphy tracked in vivo disintegration of radiolabeled tablets, and serial blood sampling determined pharmacokinetic parameters. For efficacy, pregnant rabbits received SR dydrogesterone 2 mg once daily from mating through the first trimester, followed by post-treatment ultrasonography, biochemical assays (PIBF, integrin αVβ3, VEGF), and endometrial histopathology; comparators were conventional dydrogesterone and saline control. Results: Scintigraphy revealed prolonged disintegration and sustained drug release from SR dydrogesterone. The two-fold higher tmax (6 h) of SR dydrogesterone compared to conventional (3 h), confirmed thesustained release behavior. SR dydrogesterone (34.8±5.1 ng.h/mL) demonstrated nearly 2-fold higher AUC0-48 compared to conventional dydrogesterone (14.4±2.8 ng.h/mL), however at same dose AUC0-48 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).Endometrium of animals treated with SR dydrogesterone showed dense vasculature compared to moderate for conventional dydrogesterone and low for control group animals. 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.

Keywords: Dydrogesterone, Endometrial receptivity, Pharmacokinetics, Scintigraphy, Sustained release.