Population Pharmacokinetics and Pharmacodynamics of Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction

Abstract

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.

Conflict of interest statement

Hauke Ruehs, Dagmar Klein, Matthias Frei, Corina Becker, Lothar Roessig, Dirk Garmann, and Michaela Meyer are employees and potential stockholders of Bayer AG and may own stock in the company. Joachim Grevel and Rupert Austin are employees of BAST Inc. Limited and paid consultants for Bayer Healthcare Pharmaceuticals. Burkert Pieske served as the Study Chair on the Executive Committee of SOCRATES and received advisory honoraria and speakers’ fees from Bayer Healthcare and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

© 2021. The Author(s).

Figures

Fig. 1

Flow of patients through the SOCRATES-REDUCED study and eligible samples for vericiguat pharmacokinetic (PK) and PK/pharmacodynamic (PD) analyses. HR heart rate, LLOQ lower limit of quantification, N/A not applicable, SBP systolic blood pressure

Fig. 2

Prediction-corrected visual predictive checks of the final covariate model at visits 1–5. The upper row shows the normal scale and the lower row shows the log scale of the prediction-corrected concentrations. In Visits 2–5, time is shown ± 24 h around the planned time. Solid purple line: median prediction-corrected data. Dashed purple lines: 90% prediction interval of prediction-corrected data. Solid red line: median model predictions. Solid blue lines: 90% interval. Boxes indicate the 95% confidence intervals around the corresponding model predictions. Circles: prediction-corrected observed vericiguat plasma concentration–time data

Fig. 3

Systolic blood pressure (SBP) change vs vericiguat maximum observed concentration (Cmax). Correlation of Cmax with change in SBP from pre-dose to post-dose (first dose of study medication) at visit 1. Open symbols represent data from individual patients belonging to different treatment arms (black: placebo, dark blue: 1.25 mg, teal: 2.5 mg). The red solid line depicts the linear regression model. The 95% confidence interval (CI) of the regression model is represented by red dashed lines

Fig. 4

Systolic blood pressure (SBP) change vs vericiguat maximum observed concentration at steady state (Cmax,ss). Correlation of Cmax,ss with pre-dose to post-dose change of SBP at week 8 (visit 4). Open symbols represent data from individual patients belonging to different treatment arms (black: placebo, dark blue: 1.25 mg, teal: 2.5 mg, green: 5 mg, orange: 10 mg). The red solid line depicts the linear regression model. The 95% confidence interval (CI) of the regression model is represented by dashed lines

Fig. 5

Scheme visualizing the structure of the pharmacokinetic/pharmacodynamic (PK/PD) turnover model for N-terminal pro-B-type natriuretic peptide (NT-proBNP). [NT-proBNP] is the plasma concentration of NT-proBNP, kin is a zero-order rate describing the production of NT-proBNP, and kout is a first-order rate constant describing the elimination of NT-proBNP. Area under the plasma concentration–time curve (AUC) is the exposure of vericiguat and [NT-proBNP]baseline is the NT-proBNP concentration at baseline

Fig. 6

Visual predictive check (VPC) of absolute [NT-proBNP] simulations from pharmacokinetic/pharmacodynamic (PK/PD) model with study data from SOCRATES-REDUCED stratified by the four quartiles of [NT-proBNP]baseline plasma concentration. Red lines: medians of observed data. Yellow lines: 10th and 90th percentiles of observed data. Unshaded boxes: 95% confidence intervals (CIs) around the median of simulated data. Gray shaded boxes: 95% CIs around 10th and 90th percentiles of simulated data. Blue points: observed data. NTPB0 quartile 1/2/3/4: patients assigned to first/second/third/fourth quartiles of [NT-proBNP]baseline according to fixed boundaries (94.1–1559 pg/mL, 1559–3000 pg/mL, 3000–6246 pg/mL, 6246–69,720 pg/mL). NT-proBNP N-terminal pro-B-type natriuretic peptide, [NT-proBNP]baseline concentration of NT-proBNP at baseline

Fig. 7

Simulated N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration–time profiles under vericiguat 10 mg on top of standard of care (SoC) or for SoC alone (a) and simulated absolute NT-proBNP change compared with SoC (b). Solid lines: simulated NT-proBNP time courses for vericiguat 10 mg. Dashed lines: simulations for the corresponding SoC arm. [NT-proBNP]baseline considered for simulation: 250 pg/mL (gray), 500 pg/mL (orange), 1000 pg/mL (green), 3000 pg/mL (purple), 5000 pg/mL (light blue), and 10,000 pg/mL (dark blue)

Fig. 8

Results of N-terminal pro-B-type natriuretic peptide (NT-proBNP) pharmacokinetic/pharmacodynamic (PK/PD) simulation (expressed as ratio to standard of care [SoC]) displayed as stratified boxplots. Data were assigned to first/second/third/fourth quartiles (Q1/Q2/Q3/Q4) of [NT-proBNP]baseline according to fixed boundaries (94.1–1559 pg/mL, 1559–3000 pg/mL, 3000–6246 pg/mL, and 6246–69,720 pg/mL). Blue points: median of [NT-proBNP]day84/[NT-proBNP]baseline divided by the corresponding SoC median of [NT-proBNP]day84/[NT-proBNP]baseline across patients from each simulation repeat