Safety and Exploratory Pharmacology (J.W., H.Z., A.L.) and Discovery Chemistry (G.D., S.W., J.M.), Merck Research Laboratories, Merck & Co., Inc., West Point, Pennsylvania
Safety and Exploratory Pharmacology (J.W., H.Z., A.L.) and Discovery Chemistry (G.D., S.W., J.M.), Merck Research Laboratories, Merck & Co., Inc., West Point, Pennsylvania.
J Pharmacol Exp Ther. 2024 Apr 18;389(2):229-242. doi: 10.1124/jpet.123.001858.
The drug-drug interaction (DDI) between amiodarone (AMIO) and sofosbuvir (SOF), a direct-acting hepatitis-C NS5B nucleotide polymerase inhibitor, has been associated with severe bradyarrhythmia in patients. Recent cryo-EM data has revealed that this DDI occurs at the -subunit of L-type Cav channels, with AMIO binding at the fenestration site and SOF [or MSD nucleotide inhibitor #1 (MNI-1): analog of SOF] binding at the central cavity of the conductance pathway. In this study, we investigated the DDI between 21 AMIO analogs, including dronedarone (DRON) and MNI-1 (or SOF) in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hCav1.2 models. Our findings indicate that among the tested AMIO analogs in hiPSC-CMs at clinically relevant concentrations, only three analogs (AA-9, AA-10, and AA-17) were able to effectively substitute for AMIO in this DDI with 1 M MNI-1. This highlights the importance of the diethyl amino group of AMIO for interacting with MNI-1. In the hCav1.2 model, desethylamiodarone (AA-12) demonstrated synergy with 90 M MNI-1, while three other analogs with modifications to the position of the diethyl amino group or removal of iodo groups showed weaker synergy with 90 M MNI-1. Interestingly, DRON did not exhibit any interaction with 270 M SOF or 90 M MNI-1, suggesting that it could safely replace AMIO in patients requiring SOF treatment, other clinically relevant differences considered. Overall, our functional data align with the cryo-EM data, highlighting that this DDI is dependent on the structure of AMIO and cardiomyocyte resting membrane potential. SIGNIFICANCE STATEMENT: Our findings point to specific residues in the AMIO molecule playing a critical role in the DDI between AMIO and MNI-1 (SOF analog), confirming cryo-EM results. Applied at clinically relevant AMIO's concentrations or projected MNI-1's concentrations at the resting potentials mimicking the sinoatrial node, this DDI significantly slowed down or completely inhibited the beating of hiPSC-CMs. Finally, these in vitro results support the safe replacement of AMIO (Cordarone) with DRON (Multaq) for patients requiring SOF treatment, other clinical caveats considered.
胺碘酮（AMIO）与索非布韦（SOF）之间的药物相互作用（DDI），一种直接作用的丙型肝炎 NS5B 核苷酸聚合酶抑制剂，与患者严重的心动过缓有关。最近的冷冻电镜数据显示，这种 DDI 发生在 L 型 Cav 通道的亚基上，AMIO 结合在窗格位点，SOF [或 MSD 核苷酸抑制剂 #1（MNI-1）：SOF 的类似物]结合在电导途径的中央腔中。在这项研究中，我们在人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）和 hCav1.2 模型中研究了 21 种 AMIO 类似物，包括决奈达隆（DRON）和 MNI-1（或 SOF）之间的 DDI。我们的研究结果表明，在所测试的 hiPSC-CMs 中，在临床相关浓度下，只有三种类似物（AA-9、AA-10 和 AA-17）能够在 1 M MNI-1 存在的情况下有效替代 AMIO 进行这种 DDI。这突出表明 AMIO 的二乙氨基对与 MNI-1 相互作用的重要性。在 hCav1.2 模型中，去乙基胺碘酮（AA-12）与 90 M MNI-1 表现出协同作用，而其他三种类似物中，二乙氨基的位置发生了修饰或碘基团被去除，与 90 M MNI-1 的协同作用较弱。有趣的是，DRON 与 270 M SOF 或 90 M MNI-1 均无相互作用，这表明它可以在需要 SOF 治疗的患者中安全替代 AMIO，其他临床相关差异也被考虑在内。总的来说，我们的功能数据与冷冻电镜数据一致，突出表明这种 DDI 依赖于 AMIO 的结构和心肌细胞的静息膜电位。意义陈述：我们的研究结果表明 AMIO 分子中的特定残基在 AMIO 和 MNI-1（SOF 类似物）之间的 DDI 中起着关键作用，证实了冷冻电镜结果。在模拟窦房结的静息电位下，应用于临床相关 AMIO 浓度或预测的 MNI-1 浓度，这种 DDI 显著减慢或完全抑制了 hiPSC-CMs 的搏动。最后，这些体外结果支持在需要 SOF 治疗的患者中用决奈达隆（Multaq）安全替代胺碘酮（Cordarone），其他临床注意事项也被考虑在内。
