BACKGROUND: Vericiguat, a stimulator of soluble guanylate cyclase, has been 
developed as a first-in-class therapy for worsening chronic heart failure in 
adults with left ventricular ejection fraction < 45%.
OBJECTIVE: The objective of this article was to characterize the 
pharmacokinetics and pharmacokinetic variability of vericiguat combined with 
guideline-directed medical therapy (standard of care), and identify 
exposure-response relationships for safety (hemodynamics) and pharmacodynamic 
markers of efficacy (N-terminal pro-B-type natriuretic peptide concentration 
[NT-proBNP]) in patients with heart failure and left ventricular ejection 
fraction < 45% in the SOCRATES-REDUCED study (NCT01951625).
METHODS: Vericiguat and NT-proBNP plasma concentrations in 454 and 432 patients 
in SOCRATES-REDUCED, respectively, were analyzed using nonlinear mixed-effects 
modeling.
RESULTS: Vericiguat pharmacokinetics were well described by a one-compartment 
model with apparent clearance, apparent volume of distribution, and absorption 
rate constant. Age, bodyweight, plasma bilirubin, and creatinine clearance were 
identified as significant covariates on apparent clearance; sex and bodyweight 
on apparent volume of distribution; and bodyweight and plasma albumin level on 
absorption rate constant. Pharmacokinetic/pharmacodynamic analysis showed 
initial minor and transient effects of vericiguat on blood pressure with low 
clinical impact. There were no changes in heart rate following initial or 
repeated vericiguat administration. An exposure-dependent and time-dependent 
turnover pharmacokinetic/pharmacodynamic model for NT-proBNP described 
production and elimination rates and an demonstrated exposure-dependent 
reduction in [NT-proBNP] by vericiguat plus standard of care compared with 
placebo plus standard of care. This effect was dependent on baseline 
[NT-proBNP].
CONCLUSIONS: Vericiguat has predictable pharmacokinetics, with no long-term 
effects on blood pressure in patients with heart failure and left ventricular 
ejection fraction < 45%. A pharmacokinetic/pharmacodynamic model described a 
vericiguat exposure-dependent reduction of NT-proBNP.
CLINICAL TRIAL IDENTIFIER: NCT01951625.