Yellepeddi Venkata K, Ismail Mohamed, Bunch T Jared, Deering Thomas F, Holubkov Richard, Kennedy Robert, Mittal Suneet, Perez Marco, Piccini Jonathan P, Pokharel Parash, Savona Salvatore, Verma Nishant, Steinberg Benjamin, Watt Kevin
Division of Clinical Pharmacology, Department of Pediatrics, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, Utah, USA.
Department of Molecular Pharmaceutics, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA.
CPT Pharmacometrics Syst Pharmacol. 2025 Apr;14(4):658-667. doi: 10.1002/psp4.13302. Epub 2025 Jan 3.
Sotalol, a class III antiarrhythmic agent, is used to maintain sinus rhythm in patients with atrial fibrillation or atrial flutter (AFIB/AFL). Despite its efficacy, sotalol's use is limited by its potential to cause life-threatening ventricular arrhythmias due to QT interval prolongation. Traditionally, sotalol administration required hospitalization to monitor these risks. The FDA approval of intravenous (IV) sotalol for loading before oral maintenance aims to reduce hospitalization duration by facilitating an expedited loading dose, transitioning to oral maintenance therapy. This study evaluates the population pharmacokinetics (PK) and pharmacodynamics (PD) of sotalol using data from the Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) Registry, which includes patients with atrial arrhythmias undergoing IV sotalol loading. A nonlinear mixed-effect modeling approach was used to describe sotalol PK, considering covariates such as age, weight, sex, and renal function. The study also examined the correlation between sotalol plasma concentrations and corrected QT interval (QTc) prolongation. Sotalol PK after IV loading and two oral maintenance doses was adequately described by a two-compartment model with first-order elimination in patients with atrial arrhythmias. Weight and creatinine clearance (CrCl) were identified as covariates with significant influence on sotalol PK. A linear regression model adequately described the relationship between QTc and plasma sotalol levels (R = 0.27). The Monte Carlo simulations showed that the IV loading doses recommended in the prescribing information did not result in significant prolongation of QTc. The data from this study supports the current dosing recommendations of IV sotalol in patients with AFIB/AFL.
索他洛尔是一种III类抗心律失常药物，用于维持心房颤动或心房扑动（AFIB/AFL）患者的窦性心律。尽管其疗效显著，但由于索他洛尔可导致QT间期延长，进而引发危及生命的室性心律失常，其应用受到限制。传统上，使用索他洛尔需要住院以监测这些风险。美国食品药品监督管理局（FDA）批准静脉注射（IV）索他洛尔用于口服维持前的负荷给药，旨在通过加快负荷剂量给药并过渡到口服维持治疗来缩短住院时间。本研究使用来自静脉注射索他洛尔前瞻性评估分析与动力学（PEAKS）注册研究的数据，评估索他洛尔的群体药代动力学（PK）和药效动力学（PD），该注册研究纳入了接受静脉注射索他洛尔负荷给药的房性心律失常患者。采用非线性混合效应建模方法来描述索他洛尔的PK，同时考虑年龄、体重、性别和肾功能等协变量。该研究还考察了索他洛尔血浆浓度与校正QT间期（QTc）延长之间的相关性。在房性心律失常患者中，静脉注射负荷剂量及两次口服维持剂量后的索他洛尔PK可通过具有一级消除的二室模型得到充分描述。体重和肌酐清除率（CrCl）被确定为对索他洛尔PK有显著影响的协变量。线性回归模型充分描述了QTc与血浆索他洛尔水平之间的关系（R = 0.27）。蒙特卡洛模拟显示，处方信息中推荐的静脉注射负荷剂量不会导致QTc显著延长。本研究数据支持目前AFIB/AFL患者静脉注射索他洛尔的给药建议。
