目的:这两部分,适应性研究评估了食物和酸还原剂(雷贝拉唑)对卡比塞替的药代动力学(PK)和安全性的影响,一种有效的AKT抑制剂,在癌症治疗的临床开发中。
方法:在第1部分中,健康参与者(n=24)在禁食过夜后随机接受单剂量capivasertib,高脂肪,高热量膳食和雷贝拉唑隔夜禁食是六种治疗顺序之一。根据第1部分的结果,一组新的参与者(n=24)被随机分配(第2部分)在禁食过夜后接受capivasertib,低脂肪,在六个治疗序列之一中,低热量膳食和改良的禁食(从给药前2小时到给药后1小时限制食物)。收集血液样品用于PK分析。
结果:在高脂肪之后,高热量的膳食,capivasertib暴露量与禁食过夜相比增加(几何平均比[GMR][90%置信区间(CI)]:浓度-时间曲线下面积[AUCinf]1.32[1.22,1.43],最大浓度[Cmax]1.23[1.08,1.41]),但与改良后的禁食相当(GMR:AUCinf1.13[0.99,1.29],Cmax0.85[0.70,1.04])。AUCinf相似,Cmax较低(GMR:AUCinf0.94[0.87,1.02]),Cmax0.73[0.64,0.84]).卡皮塞替在低脂肪后暴露相似,低热量膳食与隔夜禁食(GMR:AUCinf1.14[1.05,1.25],Cmax1.21[0.99,1.48])或改良空腹(GMR:AUCinf0.96[0.88,1.05],Cmax0.86[0.70,1.06])。安全性与较大试验一致。
结论:本研究表明,与食物或酸降低剂一起给药capivasertib不会导致临床相关的PK或安全性变化。
This two-part, adaptive
study assessed the effect of food and an acid-reducing agent (rabeprazole) on the pharmacokinetics (PK) and safety of capivasertib, a potent AKT inhibitor, in clinical development for cancer treatment.
In Part 1, healthy participants (n = 24) were randomized to receive single-dose capivasertib after overnight fasting, a high-fat, high-calorie meal and with rabeprazole postovernight fasting in one of six treatment sequences. Based on Part 1 results, a new group of participants (n = 24) were randomized (Part 2) to receive capivasertib after overnight fasting, a low-fat, low-calorie meal and modified fasting (food restricted from 2 h before dosing to 1 h postdose) in one of six treatment sequences. Blood samples were collected for PK analyses.
Following a high-fat, high-calorie meal, capivasertib exposure increased versus overnight fasting (geometric mean ratio [GMR] [90% confidence interval (CI)]: area under the concentration-time curve [AUCinf ] 1.32 [1.22, 1.43], maximum concentration [Cmax ] 1.23 [1.08, 1.41]), but was comparable to that postmodified fasting (GMR: AUCinf 1.13 [0.99, 1.29], Cmax 0.85 [0.70, 1.04]). AUCinf was similar and Cmax was lower with/without rabeprazole (GMR: AUCinf 0.94 [0.87, 1.02]), Cmax 0.73 [0.64, 0.84]). Capivasertib exposure was similar after a low-fat, low-calorie meal versus overnight fasting (GMR: AUCinf 1.14 [1.05, 1.25], Cmax 1.21 [0.99, 1.48]) or modified fasting (GMR: AUCinf 0.96 [0.88, 1.05], Cmax 0.86 [0.70, 1.06]). Safety was consistent with that in larger trials.
This
study demonstrates that administering capivasertib with food or acid-reducing agents does not lead to clinically relevant PK or safety profile changes.