ObsEva SA, 1228, Plan-les-Ouates, Switzerland.
Richmond Pharmacology, St. George's University London, UK.
Br J Clin Pharmacol. 2019 Jul;85(7):1516-1527. doi: 10.1111/bcp.13925. Epub 2019 May 11.
To investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard-of-care medicines for preterm labour, enabling coadministration and further clinical development.
Part A: open-label, randomized, 3-period crossover assessing coadministration of single doses of OBE022 (1100 mg) and MgSO . Part B: open-label, single-sequence crossover assessing the interactions following administration of OBE022 (1000 mg/day) at steady state coadministered with single doses of atosiban, nifedipine and betamethasone. Twenty-five healthy nonpregnant women of reproductive age were enrolled (Part A: n = 12; Part B: n = 13).
OBE022, alone or in combination with standard-of-care medications, was well tolerated. Headache and dizziness were the most frequently reported adverse events; dizziness occurred more often with the nifedipine/OBE022 combination. There were no clinically significant pharmacokinetic interactions when coadministered with MgSO . Co-administration had no notable effect on atosiban exposure. Atosiban reduced exposure to OBE002 (peak concentration [C ] 22%, area under the concentration-time curve [AUC] 19%). Coadministration with betamethasone slightly increased betamethasone exposure (C + 18%, AUC +27%) and OBE002 exposure (C + 35%, AUC +15%). These changes were not considered clinically significant. Coadministration with nifedipine slightly increased OBE002 exposure (C + 29%, AUC +24%) and markedly increased nifedipine exposure (C by 2-fold and AUC by 2-fold), which may be clinically significant.
The use of OBE022, a PGF2α antagonist prodrug, in combination with standard-of-care medicines may provide new treatment alternatives for preterm labour. All tested combinations were well tolerated. Nifedipine doses could potentially be reduced or staggered when coadministered with OBE022.
研究 OBE022 与早产标准治疗药物同时使用时是否存在临床相关的药物相互作用（药代动力学和安全性/耐受性），从而实现联合用药并进一步开展临床开发。
A 部分：开放标签、随机、3 周期交叉研究，评估单次给予 OBE022（1100mg）和硫酸镁的同时给药。B 部分：开放标签、单序列交叉研究，评估稳态下给予 OBE022（1000mg/天）与阿托西班、硝苯地平、倍他米松单次剂量同时给药时的相互作用。共纳入 25 名有生育能力的健康非妊娠女性（A 部分：n=12；B 部分：n=13）。
OBE022 单独或与标准治疗药物联合使用均具有良好的耐受性。头痛和头晕是最常报告的不良事件；硝苯地平/OBE022 联合用药时头晕更常见。与硫酸镁同时使用时，无临床显著的药代动力学相互作用。与阿托西班同时使用对 OBE002 的暴露无显著影响。阿托西班降低了 OBE002 的暴露（峰浓度 [C ]22%，浓度-时间曲线下面积 [AUC]19%）。与倍他米松同时使用略微增加了倍他米松的暴露（C 增加 18%，AUC 增加 27%）和 OBE002 的暴露（C 增加 35%，AUC 增加 15%）。这些变化被认为无临床意义。与硝苯地平同时使用略微增加了 OBE002 的暴露（C 增加 29%，AUC 增加 24%），并显著增加了硝苯地平的暴露（C 增加 2 倍，AUC 增加 2 倍），这可能具有临床意义。
PGF2α 拮抗剂前药 OBE022 与标准治疗药物联合使用可能为早产提供新的治疗选择。所有测试的组合均具有良好的耐受性。当与 OBE022 同时使用时，硝苯地平的剂量可能会减少或错开。
