Population Pharmacokinetics of Vericiguat in Patients With Heart Failure With Reduced Ejection Fraction: An Integrated Analysis

Abstract

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.

Applied physiologically‐based pharmacokinetic modeling to assess uridine diphosphate‐glucuronosyltransferase‐mediated drug–drug interactions for Vericiguat

“…UGT1A1 and UGT1A9 have known polymorphisms affecting their respective activities, 18 which was one additional aspect that was investigated in this study. Although the genetic polymorphisms of UGT1A1 and UGT1A9 were not expected to affect the PKs of vericiguat and M‐1 to a clinically relevant extent, given that the overall interindividual variability of the PK of vericiguat was found to be low to moderate throughout the vericiguat program, 3 , 57 this study intended to provide a quantitative idea of such genetic polymorphisms in a scenario‐based fashion. In general, changes in respective UGT activities led to more pronounced effects on AUC compared with the minor changes in C max for vericiguat.…”

Vericiguate: a new treatment for chronic heart failure

“…К тому же она не зависит от возраста, пола, расы, уровня в крови билирубина и альбумина, скорости клубочковой фильтрации, а также от функционального класса СН, фракции выброса левого желудочка и уровня в крови NT-proBNP. Един ствен ный фактор, влияющий на фармакокинетику верицигуата,это масса тела и ее изменения [69]. В плазме верицигуат на 98% связан с протеином (в основном альбумином), клиренс медленный (1,6 л/ч у здоровых людей), объем распределения в среднем составляет около 44 л. У здоровых людей примерно 53% дозы выводится с мочой и 45% -с калом.…”

The Evolving Role of Vericiguat in Patients With Chronic Heart Failure

“…There are also no long-term effects of vericiguat on blood pressure in patients with heart failure and left ventricular EF less than 45% [ 70 ]. Age, race, bilirubin, estimated glomerular filtration rate (eGFR), and albumin concentration do not affect the pharmacokinetics of vericiguat [ 72 ]. Literature also suggests that female patients of reproductive age should take a pregnancy test before starting vericiguat due to potential hazards to the fetus [ 67 ].…”