Estradiol valerate 1mg / Levonorgestrel 250microgram tablets

According to the FDA Guidance for Industry on Clinical Drug Interaction (DDI) Studies with Combined Oral Contraceptives (COCs), sponsors are expected to conduct dedicated clinical DDI studies if in vitro findings suggest weak or moderate CYP3A induction, while concomitant use of COCs with strong inducers should be avoided. The guidance further suggests that a negative DDI result for drospirenone (DRSP) may be extrapolated to other progestins that are less sensitive to CYP3A modulation, such as levonorgestrel (LNG). This approach assumes that DDI-mediated changes in exposure directly translate into clinical efficacy across progestins. To evaluate the validity of this assumption, we established a quantitative link between dose, exposure, and response (Pearl Index [PI] and ovulation rate [OR]) via an integrated model-based meta-analysis, physiologically based pharmacokinetic, and pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation approach using data from 51 clinical studies in 36,040 women receiving LNG or DRSP. COCs containing LNG and DRSP were selected because they represent clinically relevant progestins at the lower and the upper end of the fraction metabolized via CYP3A4. The results of our analysis show a moderate correlation (Pearson's r = 0.52, 95% CI 0.46-0.58, P < 0.001) between PI and OR, which enables the use of OR as an ethically measurable endpoint, even at subtherapeutic doses/exposures, to predict efficacy outcomes. They further show that DDI-induced changes in exposure do not directly translate into clinical response. Therefore, DDIs with COCs should be interpreted in a PK/PD rather than a PK-only context. The quantitative framework developed in this study can serve as the scientific basis to do so.

Abstract licence: CC BY

BackgroundPsychological symptoms in perimenopause and early menopause are common. The impact of menopausal hormone therapy (MHT) on menopausal mood symptoms is unclear.AimsTo assess the impact of 17β-oestradiol ± micronised progesterone or the levonorgestrel-releasing intrauterine device, and/or transdermal testosterone, on depressive and anxiety symptoms in peri- and postmenopausal women.MethodA real-world retrospective cohort study set in the largest specialist menopause clinic in the UK. The Meno-D questionnaire measured mood-related symptoms.ResultsThe study included 920 women: 448 (48.7%) perimenopausal, and 435 (47.3%) postmenopausal. Following initiation/optimisation of MHT, mean Meno-D scores decreased by 44.59% (95% CI -46.83% to -42.34%, P P v. 48.53%, respectively, P = 0.47) and MHT optimisation strategy (MHT users treated with a higher oestradiol dose versus testosterone added versus both a higher oestradiol dose and testosterone, 34.70, 43.93 and 43.25%, respectively, P = 0.38).ConclusionsUse of menopausal hormone therapy was associated with significant improvement in mood in peri- and postmenopausal women. Prospective studies and randomised clinical trials are needed to assess the effects of different regimens in different patient populations over longer time periods.

Abstract licence: CC BY