Pharmacometric analyses to characterize the effect of CSL112 on apolipoprotein A-I and cholesterol efflux capacity in acute myocardial infarction patients.
Pharmacometric analyses to characterize the effect of CSL112 on apolipoprotein A-I and cholesterol efflux capacity in acute myocardial infarction patients.
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用于表征CSL 112对急性心肌梗死患者载脂蛋白A-I和胆固醇外排能力影响的药理学分析。
DOI：
10.1111/bcp.14666
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发表时间：
2021-06
影响因子：
3.4
通讯作者：
Tortorici MA
中科院分区：
文献类型：
--
作者：
Zheng B;Duffy D;Tricoci P;Kastrissios H;Pfister M;Wright SD;Gille A;Tortorici MA
在包括急性心肌梗死（AMI）患者在内的综合人群中描述CSL 112（apoA-I [人]）给药后载脂蛋白A-I（apoA-I）暴露量与胆固醇外排能力（CEC）和协变量效应之间的关系。药理学分析利用了来自七项临床试验的数据，包括AMI患者、肾损害受试者和健康受试者。进行了群体药代动力学（PK）分析，以将CSL 112剂量与apoA-I血浆浓度变化联系起来。进行协变量分析，以确定apoA-I暴露的变异性来源。进行了暴露-反应建模，以描述apoA-I暴露与总CEC或ATP结合盒转运蛋白A1（ABCA 1）依赖性CEC之间的关系，并确定CEC的临床预测因子。两室模型描述了apoA-I PK。AMI受试者的ApoA-I清除率略低，而女性和日本受试者的基线apoA-I略高。apoA-I暴露的协变量效应约为10%，因此无临床相关性。apoA-I暴露与CEC之间的关系通过非线性模型描述。模拟显示，AMI和非AMI受试者中apoA-I暴露增量导致的CEC升高相当;无协变量对CEC产生有临床意义的影响。模拟还表明，与安慰剂和较低剂量水平相比，6 g CSL 112给药后AMI患者的CEC显著升高。基于模型的暴露量-效应分析表明，无论体重、性别和人种如何，固定6 g CSL 112给药均可引起预期的CEC升高，这可能通过潜在降低早期复发性心血管事件风险而使AMI患者获益。
To characterize relationships between apolipoprotein A‐I (apoA‐I) exposure and cholesterol efflux capacity (CEC) and covariate effects following CSL112 (apoA‐I [human]) administration in an integrated population including acute myocardial infarction (AMI) patients. A pharmacometric analysis utilized data from seven clinical trials, including patients with AMI, subjects with renal impairment and healthy subjects. A population pharmacokinetic (PK) analysis was performed to relate CSL112 doses to changes in apoA‐I plasma concentrations. Covariate analysis was conducted to identify sources of variability in apoA‐I exposure. Exposure‐response modeling was conducted to describe the relationship between apoA‐I exposure and total or ATP binding cassette transporter A1‐(ABCA1)‐dependent CEC and to identify clinical predictors of CEC. A two‐compartment model described apoA‐I PK. ApoA‐I clearance was slightly lower in subjects with AMI, whereas baseline apoA‐I was marginally higher in female and Japanese subjects. Covariate effects on apoA‐I exposure were in the order of 10% and thus not clinically relevant. The relationships between apoA‐I exposure and CECs were described by nonlinear models. Simulations showed CEC elevation resulting from apoA‐I exposure increment was comparable in AMI and non‐AMI subjects; no covariate had clinically meaningful effects on CEC. Simulations also demonstrated that CEC in patients with AMI post 6 g CSL112 dosing was substantially elevated compared to placebo and lower dose levels. The model‐based exposure‐response analysis demonstrated, irrespective of body weight, sex and race, that fixed 6 g CSL112 dosing causes a desired CEC elevation, which may benefit AMI patients by potentially reducing early recurrent cardiovascular event risk.
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