Background

Vericiguat is a stimulator of soluble guanylate cyclase currently under investigation as a first-in-class therapy for worsening chronic heart failure (NCT02861534). Patients with heart failure often require polypharmacy because of comorbidities. Hence, understanding the clearance mechanisms, elimination, and potential for pharmacokinetic drug–drug interactions of vericiguat is important for dose recommendations in this patient population.

Methods

Biotransformation and perpetrator properties of vericiguat were characterized in vitro using human hepatocytes, liver microsomes, and recombinant enzymes. This was complemented by a human mass balance study and ten drug–drug interaction studies in healthy volunteers wherein vericiguat was co-administered orally with omeprazole, magnesium/aluminum hydroxide, ketoconazole, rifampicin, mefenamic acid, midazolam, warfarin, digoxin, sacubitril/valsartan, aspirin, or sildenafil.

Results

In the human mass balance study, mean total radioactivity recovered was 98.3% of the dose administered (53.1% and 45.2% excreted via urine and feces, respectively). The main metabolic pathway of vericiguat is glucuronidation via uridine diphosphate-glucuronosyltransferase 1A9 and 1A1. In vitro studies revealed a low risk of vericiguat acting as a perpetrator by inhibiting cytochrome P450s, uridine diphosphate-glucuronosyltransferase isoforms, or major transport proteins, or by inducing cytochrome P450s. These observations were supported by phase I drug–drug interaction studies. Phase I studies that assessed the propensity of vericiguat as a victim drug showed changes in the range that did not warrant recommendations for dose adjustment in phase III.

Conclusions

A low pharmacokinetic interaction potential of vericiguat was estimated from in vitro data and confirmed in vivo. Thus, vericiguat is suitable for a patient population with multiple comorbidities requiring polypharmacy.

中文翻译：

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Vericiguat（一种可溶性鸟苷酸环化酶刺激剂）的代谢和药代动力学药物相互作用特征：临床前和 I 期健康志愿者研究的结果。

背景

Vericiguat 是一种可溶性鸟苷酸环化酶刺激剂，目前正在研究中作为治疗慢性心力衰竭恶化的一流疗法 (NCT02861534)。由于合并症，心力衰竭患者通常需要多种药物治疗。因此，了解vericiguat 的清除机制、消除和药代动力学药物-药物相互作用的潜力对于该患者人群的剂量建议很重要。

方法

使用人肝细胞、肝微粒体和重组酶在体外表征了 vericiguat 的生物转化和肇事者特性。一项人体质量平衡研究和 10 项健康志愿者的药物相互作用研究对此进行了补充，其中 vericiguat 与奥美拉唑、镁/氢氧化铝、酮康唑、利福平、甲芬那酸、咪达唑仑、华法林、地高辛、沙库巴曲/缬沙坦共同口服给药、阿司匹林或西地那非。

结果

在人体质量平衡研究中，回收的平均总放射性为给药剂量的 98.3%（分别通过尿液和粪便排出 53.1% 和 45.2%）。vericiguat 的主要代谢途径是通过尿苷二磷酸-葡萄糖醛酸转移酶 1A9 和 1A1 进行葡萄糖醛酸化。体外研究表明，vericiguat 通过抑制细胞色素 P450、尿苷二磷酸-葡萄糖醛酸转移酶同种型或主要转运蛋白，或通过诱导细胞色素 P450，作为肇事者的风险很低。这些观察结果得到了 I 期药物-药物相互作用研究的支持。I 期研究评估了 Vericiguat 作为受害者药物的倾向，显示范围的变化不值得推荐 III 期的剂量调整。

结论

vericiguat 的低药代动力学相互作用潜力是根据体外数据估计的，并在体内得到证实。因此，vericiguat 适用于需要多药治疗的多种合并症患者。