Richmond Pharmacology Ltd., St George's University of London, Cranmer Terrace, London, SW17 0RE, UK.
Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, UK.
Sci Rep. 2021 Mar 18;11(1):6404. doi: 10.1038/s41598-021-85650-3.
Nolasiban is an orally active oxytocin receptor antagonist being developed to increase the efficiency of assisted reproductive technologies. This study evaluated the pharmacokinetics, pharmacodynamics, and cardiac safety of nolasiban in 45 healthy women of child-bearing age. Nolasiban was administered in a fasted state with a standardised lunch served 4.5 h post-dose. Concentration-effect modelling was used to assess the effect of two dosages of nolasiban (900 mg and 1800 mg) on QTc following single-dose administration. We found no significant change in QTc at all tested dosages. Two-sided 90% confidence intervals of geometric mean C for estimated QTc effects of nolasiban were below the threshold of regulatory concern. The sensitivity of the assay to detect small changes in QTc was confirmed by a significant shortening of QTc between 2 and 4 h after consumption of a meal, which served to validate the model. Independent of the nolasiban assessment, this study also explored the effects of sex hormones on ECG parameters, especially QT subintervals. We found a significant relationship between JTpc and oestradiol. Heart rate was negatively correlated with progesterone. This study confirms the cardiovascular safety of nolasiban and describes relationships of sex hormones and ECG parameters.
那洛昔班是一种口服活性的催产素受体拮抗剂，用于提高辅助生殖技术的效率。本研究评估了在 45 名育龄健康女性中那洛昔班的药代动力学、药效学和心脏安全性。那洛昔班在禁食状态下给药，并在给药后 4.5 小时给予标准午餐。浓度-效应模型用于评估单次给药后两种剂量的那洛昔班（900mg 和 1800mg）对 QTc 的影响。我们发现所有测试剂量的 QTc 均无显著变化。估计那洛昔班 QTc 效应的几何均数 C 的双侧 90%置信区间低于监管关注的阈值。通过餐后 2 至 4 小时 QTc 的显著缩短，证实了该检测方法对 QTc 微小变化的敏感性，从而验证了该模型。本研究还独立于那洛昔班评估，探索了性激素对心电图参数，特别是 QT 间期的影响。我们发现 JTpc 与雌二醇之间存在显著关系。心率与孕激素呈负相关。本研究证实了那洛昔班的心血管安全性，并描述了性激素和心电图参数之间的关系。
