Pohl O, Homery M-C, Lemaux F, Patat A, Chollet A
ObsEva SA, Plan-les-Ouates, Geneva, Switzerland.
J Clin Pharm Ther. 2015 Jun;40(3):328-32. doi: 10.1111/jcpt.12258. Epub 2015 Feb 26.
To treat preterm labour, antenatal corticosteroids and tocolytics are often co-administered. OBE001 is an orally active oxytocin receptor antagonist under development for preterm labour treatment.
Co-administration of OBE001 and betamethasone to determine pharmacokinetic interactions was studied during an open-label, randomized, three-period crossover study. Twelve healthy post-menopausal volunteers received either two consecutive OBE001 administrations of 600 mg/day, two intramuscular injections of 12 mg/day betamethasone or the two drugs administered in combination. The area under the plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax) and the time to Cmax (tmax) for OBE001 and betamethasone were measured.
There was no effect on geometric mean Cmax after the second administration and AUCs of OBE001 [geometric mean ratio point estimate (90% CI): Cmax (Day2) 1·05 (0·98-1·12) and AUC(0-24 h )1·11 (0·99-1·23)/AUC(24 h-∞) 0·99 (0·93-1·06), respectively]; Cmax after the first administration together with betamethasone was increased by 12% [geometric mean ratio point estimates (90% CI): Cmax (Day1) 1·12 (0·96-1·32)]. Tmax after concomitant administration with betamethasone occurred with a median delay of 1 h. Geometric mean Cmax and AUCs of betamethasone were not affected by concomitant OBE001 administration [geometric mean ratio point estimate (90% CI): Cmax (Day1) 1·02 (0·98-1·07)/Cmax (Day2) 1·03 (0·98-1·08) and AUC(0-24 h) 1·07 (1·04-1·11)/AUC(24 h-∞ )1·04 (1·01-1·08), respectively], with no effect on median tmax . No subject was discontinued from the study due to adverse events.
AUC and Cmax of the betamethasone and OBE001 combination did not differ significantly between treatments. Co-administration of OBE001 and betamethasone was well tolerated and resulted in a tmax median delay of 1 h for OBE001 but not for betamethasone. Co-administration of OBE001 and betamethasone in clinics is feasible and does not require any specific precaution or administration adaptation.
为治疗早产，产前糖皮质激素和宫缩抑制剂常联合使用。OBE001是一种口服活性催产素受体拮抗剂，正在研发用于治疗早产。
在一项开放标签、随机、三阶段交叉研究中，研究了OBE001与倍他米松联合使用时的药代动力学相互作用。12名健康的绝经后志愿者分别接受连续两次600mg/天的OBE001给药、两次12mg/天的倍他米松肌肉注射或两种药物联合给药。测量了OBE001和倍他米松的血浆浓度-时间曲线下面积（AUC）、最大血浆浓度（Cmax）和达峰时间（tmax）。
第二次给药后，对OBE001的几何平均Cmax和AUCs无影响[几何平均比值点估计值（90%置信区间）：Cmax（第2天）1.05（0.98-1.12）和AUC(0-24 h)1.11（0.99-1.23）/AUC(24 h-∞)0.99（0.93-1.06）]；第一次给药时与倍他米松联合使用后，Cmax增加了12%[几何平均比值点估计值（90%置信区间）：Cmax（第1天）1.12（0.96-1.32）]。与倍他米松联合给药后，OBE001的tmax中位数延迟1小时。倍他米松的几何平均Cmax和AUCs不受OBE001联合给药的影响[几何平均比值点估计值（90%置信区间）：Cmax（第1天）1.02（0.98-1.07）/Cmax（第2天）1.03（0.98-1.08）和AUC(0-24 h)1.07（1.04-1.11）/AUC(24 h-∞)1.04（1.01-1.08）]，对tmax中位数无影响。没有受试者因不良事件而退出研究。
倍他米松和OBE001联合使用时，不同治疗组之间的AUC和Cmax无显著差异。OBE001与倍他米松联合给药耐受性良好，导致OBE001的tmax中位数延迟1小时，但倍他米松无此现象。在临床中联合使用OBE001和倍他米松是可行的，不需要任何特殊预防措施或给药调整。
