Marcantonio Eugene E, Ballard Jeanine, Gibson Christopher R, Kassahun Kelem, Palamanda Jairam, Tang Cuyue, Evers Raymond, Liu Chengcheng, Zajic Stefan, Mahon Chantal, Mostoller Kate, Hreniuk David, Mehta Anish, Morris Denise, Wagner John A, Stoch S Aubrey
Merck Sharp & Dohme, Whitehouse Station, NJ.
J Clin Pharmacol. 2014 Nov;54(11):1280-9. doi: 10.1002/jcph.338. Epub 2014 Jun 25.
We evaluated the effect of prednisone on midazolam and odanacatib pharmacokinetics. In this open-label, 2-period crossover study in healthy male subjects, midazolam 2 mg was administered (Day -1) followed by odanacatib 50 mg (Day 1) during Part 1. In Period 2, prednisone 10 mg once daily (qd) was administered on Days 1-28; odanacatib was co-administered on Day 14 and midazolam 2 mg was co-administered on Days 1 and 28. Subjects were administered midazolam 2 mg on Days 42 and 56. Safety and tolerability were assessed throughout the study. A physiologically-based pharmacokinetic (PBPK) model was also built. There were 15 subjects enrolled; mean age was 31 years. The odanacatib AUC(0- ∞) GMR (90% CI) [odanacatib + prednisone (Day 14, Period 2)/odanacatib alone (Day 1, Period 1] was 1.06 (0.96, 1.17). AUC(0-∞) GMR (90%CI) [midazolam + prednisone (Day 28, Period 2)/midazolam alone (Day -1, Period 1] was 1.08 (0.93,1.26). There were no serious AEs or AEs leading to discontinuation. PBPK modeling showed that prednisone does not cause significant effects on the exposure of sensitive CYP3A4 substrates in vivo at therapeutic doses. Co-administration of prednisone 10 mg qd had no effect on pharmacokinetics of either odanacatib 10 mg or midazolam 2 mg.
我们评估了泼尼松对咪达唑仑和奥丹卡替药代动力学的影响。在这项针对健康男性受试者的开放标签、两阶段交叉研究中，第1阶段于第-1天给予2 mg咪达唑仑，随后于第1天给予50 mg奥丹卡替。在第2阶段，第1 - 28天每天一次给予10 mg泼尼松；第14天联合给予奥丹卡替，第1天和第28天联合给予2 mg咪达唑仑。在第42天和第56天给予受试者2 mg咪达唑仑。在整个研究过程中评估安全性和耐受性。还建立了基于生理学的药代动力学（PBPK）模型。共纳入15名受试者；平均年龄为31岁。奥丹卡替的AUC(0 - ∞)几何平均比值（GMR）（90%置信区间）[奥丹卡替 + 泼尼松（第2阶段第14天）/单独使用奥丹卡替（第1阶段第1天）]为1.06（0.96，1.17）。AUC(0 - ∞) GMR（90%置信区间）[咪达唑仑 + 泼尼松（第2阶段第28天）/单独使用咪达唑仑（第1阶段第-1天）]为1.08（0.93，1.26）。未出现严重不良事件或导致停药的不良事件。PBPK模型显示，治疗剂量的泼尼松在体内对敏感的CYP3A4底物暴露无显著影响。每天一次联合给予10 mg泼尼松对10 mg奥丹卡替或2 mg咪达唑仑的药代动力学均无影响。
