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Abstract：
Vericiguat is an oral soluble guanylate cyclase stimulator and enhances the cyclic guanosine monophosphate pathway independently of nitric oxide as well as synergistically in normal- and low-nitric oxide conditions. This review describes the pharmacokinetic and pharmacodynamic profile of vericiguat and summarizes the effect of vericiguat on cardiac electrophysiology and population pharmacokinetic/pharmacodynamic relationships. Vericiguat demonstrates virtually complete absorption and increased exposure with food. Vericiguat has high oral bioavailability when taken with food (93.0%) with dose-proportional pharmacokinetics in healthy volunteers. Vericiguat has slightly less than dose-proportional pharmacokinetics with a slight decrease in bioavailability at higher doses in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Vericiguat is a low-clearance drug, with a half-life of approximately 20 h in healthy volunteers and 30 h in patients with HFrEF. Most drug metabolism is achieved by glucuronidation. Vericiguat has pharmacodynamic effects as expected from its pharmacological mechanism of action (i.e., relaxation of the smooth muscles in the vasculature leading to changes in hemodynamics). In the VICTORIA trial (NCT02861534), which enrolled patients with HFrEF, no meaningful exposure-response relationships for the incidence of symptomatic hypotension or syncope were evident. There were no significant imbalances in the incidence of undesirable hemodynamic-related effects (symptomatic hypotension and syncope) in subgroups with HFrEF defined by sex, age, race, and renal impairment. In addition, most patients achieved the 10-mg target dose per the blood pressure-guided titration regimen. No dose adjustments due to body weight, age, sex, race, or hepatic/renal impairment are necessary in adult patients with HFrEF. Observed and predicted changes in vericiguat exposure when co-administered with perpetrator drugs were small and not clinically meaningful. In addition, vericiguat has low potential as a perpetrator to affect exposure and/or pharmacodynamic effects of drugs commonly prescribed in patients with heart failure; therefore, no dose adjustment of these drugs is required in patients taking vericiguat. There is limited experience on the combined use of vericiguat with long-acting nitrates in patients with HFrEF. The ongoing VICTOR trial (NCT05093933), which is investigating vericiguat in patients with HFrEF, permits the co-administration of long-acting nitrates. Combined use of vericiguat and phosphodiesterase type-5 inhibitors has not been studied in patients with HFrEF and is therefore not recommended because of the potential increased risk for symptomatic hypotension. Vericiguat was not associated with electrophysiological abnormalities in preclinical and clinical studies up to the approved dose of 10 mg at steady state. Vericiguat is approved for the treatment of recently decompensated patients with worsening HFrEF. Vericiguat\'s safety and efficacy profile in patients with HFrEF will be further characterized by the VICTOR trial (NCT05093933) in adults without recent decompensation and in a pediatric population with HF due to left ventricular systolic dysfunction (VALOR trial, NCT05714085).
摘要：
Vericiguat是一种口服可溶性鸟苷酸环化酶刺激剂，可独立于一氧化氮以及在正常和低一氧化氮条件下协同增强环磷酸鸟苷途径。这篇综述描述了Vericiguat的药代动力学和药效学特征，并总结了Vericiguat对心脏电生理和群体药代动力学/药效学关系的影响。Vericiguat显示出几乎完全的吸收和增加的食物暴露。Vericiguat与食物一起服用时具有很高的口服生物利用度（93.0％），在健康志愿者中具有与剂量成比例的药代动力学。Vericiguat的药代动力学略低于剂量比例，在射血分数降低（HFrEF）的心力衰竭（HF）患者中，较高剂量的生物利用度略有降低。Vericiguat是一种低清除率药物，健康志愿者的半衰期约为20小时，HFrEF患者的半衰期约为30小时。大多数药物代谢是通过葡糖醛酸化实现的。Vericiguat具有预期的药效学作用（即，血管平滑肌的松弛导致血液动力学的变化）。在维多利亚试验（NCT02861534）中，招募HFrEF患者，对于症状性低血压或晕厥的发生率,没有明显的有意义的暴露-反应关系.在按性别定义的HFrEF亚组中，不良血流动力学相关效应（症状性低血压和晕厥）的发生率无明显失衡，年龄,种族,和肾功能损害。此外,根据血压引导滴定方案,大多数患者达到了10mg目标剂量.由于体重没有剂量调整，年龄,性别,种族,或肝/肾损害是必要的成人患者HFrEF。与犯罪者药物共同给药时观察到的和预测的Vericiguat暴露变化很小，没有临床意义。此外,Vericiguat作为犯罪者影响心力衰竭患者常用药物的暴露和/或药效学效应的可能性较低;因此，服用Vericiguat的患者不需要调整这些药物的剂量。在HFrEF患者中联合使用Vericiguat与长效硝酸盐的经验有限。正在进行的VICTOR试验（NCT05093933），正在研究HFrEF患者的Vericiguat，允许长效硝酸盐的共同给药。尚未在HFrEF患者中研究联合使用Vericiguat和5型磷酸二酯酶抑制剂，因此不推荐使用，因为有症状性低血压的潜在风险增加。Vericiguat在临床前和临床研究中与电生理异常无关，直到在稳态下批准的剂量为10mg。Vericiguat被批准用于治疗HFrEF恶化的最近代偿失调的患者。Vericiguat在HFrEF患者中的安全性和有效性将通过VICTOR试验（NCT05093933）在近期没有失代偿的成人和因左心室收缩功能障碍而患有HF的儿科人群中进一步表征（VALOR试验，NCT05714085)。
