Palaparthy Rameshraja, Banfield Christopher, Alvarez Paco, Yan Lucy, Smith Brian, Johnson Jessica, Monsalvo Maria Laura, Malik Fady
Int J Clin Pharmacol Ther. 2016 Mar;54(3):217-27. doi: 10.5414/CP202458.
Omecamtiv mecarbil is a novel small molecule that directly activates cardiac myosin and increases cardiac contractility without increasing cardiac myocyte intracellular calcium. This study evaluated the relative bioavailability, food effect, and safety of several modified-release (MR) formulations of omecamtiv mecarbil.
This was a phase 1, randomized, open-label, 4-way crossover, incomplete block-design study evaluating 5 MR formulations of omecamtiv mecarbil vs. an immediate-release (IR) formulation.
Healthy subjects were randomized to 1 of 30 possible sequences: within each sequence, subjects were assigned to receive a single 25-mg dose of 2 of the 6 possible formulations in the fasting and/or fed states.
65 subjects were screened and enrolled; 5 were replacement subjects. Pharmacokinetic and safety data were analyzed from 62 and 63 subjects in the fasting and fed states, respectively. Compared with the IR formulation, median t(max) was longer (0.5 vs. 2 - 10 hours), and mean C(max) was lower for all 5 MR formulations (262 vs. 34 - 78 ng/mL); t(1/2,z) was similar (18 - 21 hours). The relative bioavailability was high (> 75%) for three MR formulations but lower (< 65%) for the other two. Overall, the effect of food on omecamtiv mecarbil pharmacokinetics was minimal for four of the MR formulations. The pharmacokinetics of the inactive metabolites M3 and M4 were similar across all formulations.
The relative bioavailability of omecamtiv mecarbil was high (> 75%) for 3 of the five MR formulations. Food had a marginal, nonclinically meaningful effect on the pharmacokinetics of the MR formulations of omecamtiv mecarbil.
奥米卡替麦卡比是一种新型小分子，可直接激活心肌肌球蛋白并增强心肌收缩力，而不增加心肌细胞内钙含量。本研究评估了奥米卡替麦卡比几种缓释（MR）制剂的相对生物利用度、食物影响及安全性。
这是一项1期随机、开放标签、4交叉、不完全区组设计研究，评估奥米卡替麦卡比的5种MR制剂与速释（IR）制剂。
健康受试者被随机分配到30种可能序列中的一种：在每个序列中，受试者被指定在禁食和/或进食状态下接受6种可能制剂中2种的单次25mg剂量。
筛选并纳入65名受试者；5名为替换受试者。分别对禁食和进食状态下的62名和63名受试者的药代动力学和安全性数据进行了分析。与IR制剂相比，所有5种MR制剂的中位t(max)更长（0.5对2 - 10小时），平均C(max)更低（262对34 - 78 ng/mL）；t(1/2,z)相似（18 - 21小时）。三种MR制剂的相对生物利用度较高（> 75%），但另外两种较低（< 65%）。总体而言，对于四种MR制剂，食物对奥米卡替麦卡比药代动力学的影响极小。所有制剂中无活性代谢物M3和M4的药代动力学相似。
五种MR制剂中有三种奥米卡替麦卡比的相对生物利用度较高（> 75%）。食物对奥米卡替麦卡比MR制剂的药代动力学有轻微的、临床无意义的影响。
