P–619 Oral dydrogesterone (OD) versus micronized vaginal progesterone (MVP) for luteal phase support (LPS) in IVF/ICSI: a double blind, cross-over, pharmacokinetic study

Abstract

Abstract Study question How does the blood pharmacokinetic (PK) profile of OD/MVP differ after the first and last administration dose when used as LPS for fresh embryo transfer? Summary answer: The PK profile differed strongly between both LPS administration strategies with a more rapid absorption, metabolism and clearance of OD in comparison with MVP. What is known already Adequate LPS is crucial to achieve a successful pregnancy following ovarian stimulation (OS) and fresh embryo transfer. OD has been proven to be non-inferior compared to MVP in two phase III clinical trials. Additionally, a combined individual participant data and aggregate data meta-analysis showed an odds ratio in favor of OD for live birth. Little information is available on the PK of LPS strategies, leaving an important field unexplored. Individualization of LPS has recently gained more interest and insight into the PK of progestogens is essential to correctly interpret the potential impact of circulating hormone levels on reproductive outcomes. Study design, size, duration Twenty oocyte donors underwent two OS cycles followed by one week of LPS (OD or MVP) in a randomized, cross-over, double blind, double dummy fashion. As both dydrogesterone (D) and 20αdihydrodydrogesterone (DHD) are progestogenic, D, DHD and progesterone (P) plasma levels were established using a validated liquid chromatography tandem mass spectrometry assay in each cycle, on the 1st (single dose PK) and 8th day (multiple dose PK) of LPS (9 and 12 harvesting time-points, respectively). Participants/materials, setting, methods All oocyte donors were <35 years, had regular menstrual cycles, no intra-uterine contraceptive device, AMH within normal range and BMI ≤ 29 kg/m2. OS was performed in a GnRH antagonist protocol followed by dual triggering (1000U hCG + 0.2mg triptorelin) as soon as ≥ 3 follicles of 20mm were present. Following oocyte retrieval, subjects initiated LPS consisting of MVP 200 mg (Utrogestan®) or OD 10 mg (Duphaston®), both three times daily. Main results and the role of chance The mean (±SD) age of the subjects was 27.4 (± 3.8) years and BMI was 24.0 (±3.2) kg/m2. The mean (±SD) number of oocytes retrieved was 19.7 ±10. No adverse events were reported during the intake of the study medication. The PK results are best estimates as sampling was reduced compared to a formal PK study. Following the intake of the first dose of OD, the observed maximal plasma concentrations (Cmax) for D and DHD were 2.9 and 77 ng/ml (single dose). The Cmax for D and DHD was reached after 1.5 and 1.6 hours (=Tmax), respectively. On the 8th day of LPS the first administration of that day gave rise to a Cmax of 3.6 and 88 ng/ml for D and DHD (multiple dose). For both, the observed Tmax was 1.5 hours. Following the intake of the first dose of MVP, the Cmax for P was 16 ng/mL with a Tmax of 4.2 hours. On the 8th day of LPS the first administration of that day showed a Cmax for P of 21 ng/mL with a Tmax of 7.3 hours. Although low, the role of chance could be influenced by the relatively low sampling numbers and frequency. Limitations, reasons for caution Peripheral concentrations do not necessarily reflect the steroidogenic effect on endometrial progesterone receptors. Extrapolation to clinical practice is therefore difficult, however, molecular analyses of endometrial tissue harvested within this study protocol are underway to investigate further pharmacodynamics and the progestogenic impact on endometrial receptivity during the embryo implantation period. Wider implications of the findings: This is the first study comparing OD/MVP pharmacokinetics in IVF/ICSI. Results suggest administration frequency to be as important as dose, definitely for OD, showing a rapid absorption/clearance. More studies are needed to investigate blood levels in relation to time of LPS administration, especially in (artificially prepared) FET and LPS individualization. Trial registration number EUDRACT 2018–000105–23