Merck & Co., Inc., Rahway, New Jersey, USA.
Cognigen Corporation, a Simulations Plus Company, Buffalo, New York, USA.
Clin Pharmacol Ther. 2022 Nov;112(5):1061-1069. doi: 10.1002/cpt.2712. Epub 2022 Aug 13.
Vericiguat, a novel stimulator of soluble guanylate cyclase (sGC), is indicated for the treatment of patients following a hospitalization for heart failure or need for outpatient intravenous diuretics, with symptomatic chronic heart failure and ejection fraction less than 45%. Pharmacokinetic (PK) data from the phase II trial SOCRATES-REDUCED (Soluble Guanylate Cyclase Stimulator in Heart Failure Study) and the phase III trial VICTORIA (Vericiguat Global Study in Patients With Heart Failure With Reduced Ejection Fraction) were used to characterize vericiguat PK. A total of 8,092 concentration records from 2,321 participants (362 from SOCRATES-REDUCED and 1,959 from VICTORIA) were utilized for the development of the population PK model. The final PK model was a one-compartment model with first-order absorption and linear elimination. Baseline body weight and time-varying body weight were identified as statistically significant covariates affecting apparent clearance (CL/F) and volume of distribution, respectively. Age, sex, race, bilirubin, estimated glomerular filtration rate, and albumin did not affect vericiguat PK. Baseline disease-related factors, such as left ventricular ejection fraction, New York Heart Association (NYHA) class, and N-terminal pro B-type natriuretic peptide, also did not influence vericiguat PK. Since vericiguat is a titrated drug, the impact of vericiguat PK on the titration to and maintenance of the target dose in VICTORIA was assessed. The distribution of steady-state doses in VICTORIA was similar across CL/F quartiles, suggesting that the ability to reach and maintain dosing at the target 10-mg dose was not related to vericiguat exposure.
维立西呱，一种新型可溶性鸟苷酸环化酶（sGC）刺激剂，适用于因心力衰竭住院或需要门诊静脉利尿剂治疗、有症状的慢性心力衰竭和射血分数低于 45%的患者。来自 II 期试验 SOCRATES-REDUCED（心力衰竭患者可溶性鸟苷酸环化酶刺激剂研究）和 III 期试验 VICTORIA（维立西呱在射血分数降低的心力衰竭患者中的全球研究）的药代动力学（PK）数据用于描述维立西呱 PK。共利用来自 2321 名参与者（SOCRATES-REDUCED 组 362 名，VICTORIA 组 1959 名）的 8092 个浓度记录来建立群体 PK 模型。最终 PK 模型为一室模型，具有一级吸收和线性消除。基线体重和时变体重被确定为影响表观清除率（CL/F）和分布容积的统计学显著协变量。年龄、性别、种族、胆红素、估计肾小球滤过率和白蛋白不影响维立西呱 PK。基线疾病相关因素，如左心室射血分数、纽约心脏协会（NYHA）分级和 N 末端 pro B 型利钠肽，也不影响维立西呱 PK。由于维立西呱是一种滴定药物，因此评估了 VICTORIA 中维立西呱 PK 对滴定和维持目标剂量的影响。VICTORIA 中稳态剂量的分布在 CL/F 四分位区间相似，表明达到和维持目标 10mg 剂量的能力与维立西呱暴露无关。
