服用环硅酸锆钠后血清钾的群体药效剂量反应分析

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Clinical Pharmacokinetics Pub Date : 2024-04-01 Epub Date: 2024-03-19 DOI:10.1007/s40262-024-01360-9
Robert C Penland, Magnus Åstrand, David W Boulton, Mats Någård
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引用次数: 0

摘要

背景:环硅酸锆钠(SZC)是一种已获批准的治疗高钾血症的口服药物,它能选择性地与胃肠道中的钾(K+)结合,并通过增加粪便排泄将K+排出体外。在此,我们描述了接受 SZC 治疗的高钾血症患者血清 K+ 浓度的群体药效学(PopPD)反应,估计了患者内在和外在因素的影响,并比较了 5 克每日交替(QOD)和 2.5 克每日一次(QD)维持剂量的预测血清 K+ 反应:PopPD分析基于七项SZC II期和III期临床试验的汇总数据。采用半机制纵向混合效应(基础)模型来描述服用 SZC 后血清 K+ 浓度的特征。采用间接反应、虚拟药代动力学-药效学(PK-PD)模型模拟药物暴露区。全协变量模型用于评估协变量对半数最大有效药物浓度(EC50)、安慰剂反应和 Kout 的影响。使用拟合优度图、相对标准误差和视觉预测检查对模型进行了评估,并对数据进行了分层,以优化各分组的模型性能。根据校正期用药(48 小时,SZC 10 克,一天三次)和维持期用药(28 天,SZC 10 克,一天三次)结束时血清 K+ 在基线和参考对象之间的变化幅度来评估协变量效应:分析数据集包括 2369 名患者和 25,764 个血清 K+ 观察值。患者平均年龄(标准差)为 66.0 (12) 岁,61% 为男性,68% 为白人,34% 患有充血性心力衰竭,62% 患有糖尿病。基线血清 K+ 平均值(标准差)为 5.49 (0.43) mmol/L。基础模型和完全协方差模型都能充分描述观察到的数据。在最终模型中,Kin 的暴露反应呈弧形,EC50 为 32.8 克,希尔系数为 1.36。在校正和维持阶段,预测的安慰剂调整剂量-血清 K+ 变化反应近似线性。在 SZC 5 克/天(QOD)和 2.5 克/天(QD)的维持治疗方案之间,经安慰剂调整的血清 K+ 变化在 28 天时与基线相比没有发现有临床意义的差异。与参照患者相比,基线血清 K+较高、年龄较大、体重较轻、估计肾小球滤过率较低以及黑人/非洲裔美国人和亚洲人种的 SZC 治疗反应更大。心力衰竭状态和糖尿病状态的影响很小:SZC的PopPD模型充分描述了纠正和维持阶段用药期间血清K+浓度的变化。更大的治疗反应与各种协变量有关,但每种协变量的影响都不大。总体而言,这些研究结果表明,无需根据评估的任何协变量调整 SZC 的剂量。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Population Pharmacodynamic Dose-Response Analysis of Serum Potassium Following Dosing with Sodium Zirconium Cyclosilicate.

Population Pharmacodynamic Dose-Response Analysis of Serum Potassium Following Dosing with Sodium Zirconium Cyclosilicate.

Background: Sodium zirconium cyclosilicate (SZC) is an approved oral treatment for hyperkalemia that selectively binds potassium (K+) in the gastrointestinal tract and removes K+ from the body through increased fecal excretion. Here, we describe the population pharmacodynamic (PopPD) response of serum K+ concentration in patients with hyperkalemia who are treated with SZC, estimate the impact of patients' intrinsic and extrinsic factors, and compare predicted serum K+ responses between 5 g alternate daily (QOD) and 2.5 g once daily (QD) maintenance doses.

Methods: PopPD analysis was based on pooled data from seven phase II and III clinical trials for SZC. A semi-mechanistic longitudinal mixed-effects (base) model was used to characterize serum K+ concentration after SZC dosing. Indirect-response, virtual pharmacokinetics-pharmacodynamics (PK-PD) modeling was used to mimic the drug exposure compartment. Full covariate modeling was used to assess covariate impact on the half-maximal effective concentration of drug (EC50), placebo response, and Kout. Models were evaluated using goodness-of-fit plots, relative standard errors, and visual predictive checks, and data were stratified to optimize model performance across subgroups. Covariate effects were evaluated based on the magnitude of change in serum K+ between baseline and end of correction phase dosing (48 h, SZC 10 g three times a day) and maintenance phase dosing (28 days, SZC 10 g QD) using a reference subject.

Results: The analysis data set included 2369 patients and 25,764 serum K+ observations. The mean (standard deviation) patient age was 66.0 (12) years, 61% were male, 68% were White, 34% had congestive heart failure, and 62% had diabetes. Mean (standard deviation) serum K+ at baseline was 5.49 (0.43) mmol/L. Both the base and full covariance models adequately described observed data. In the final model, there was a sigmoid exposure response on Kin, with EC50 of 32.8 g and a Hill coefficient of 1.36. The predicted placebo-adjusted dose-responses of serum K+ change appeared nearly linear in the correction and maintenance phases. No clinically meaningful difference in placebo-adjusted serum K+ change from baseline at 28 days was observed between maintenance regimens of SZC 5 g QOD and 2.5 g QD. A greater SZC treatment response was associated with high serum K+ at baseline, advanced age, lower body weight, lower estimated glomerular filtration rate, and Black/African American and Asian race, compared with the reference patient. The impact of heart failure status and diabetes status was only minor.

Conclusions: The PopPD model of SZC adequately described changes in serum K+ concentration during correction and maintenance phase dosing. A greater treatment response was associated with various covariates, but the impact of each was modest. Overall, these findings suggest that no adjustment in SZC dose is needed for any of the covariates evaluated.

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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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