Population Pharmacokinetics and Pharmacodynamics of Cinaciguat, a Soluble Guanylate Cyclase Activator, in Patients with Acute Decompensated Heart Failure

Abstract

Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase activator in clinical development for the treatment of acute decompensated heart failure (ADHF). In patients with ADHF, intravenously administered cinaciguat results in potent unloading of the heart with arterial vasodilation. The aims of this study were to define the structural pharmacokinetic and pharmacodynamic models of cinaciguat in patients with ADHF, to characterize interindividual variability and to explore the effects of potential covariates. Modelling was performed using NONMEM version V software, based on data from 56 adult patients with ADHF (pulmonary capillary wedge pressure > or = 18 mmHg) participating in a phase II study. Cinaciguat pharmacokinetics were well described using an open, two-compartment model with an 'effect compartment' and elimination from the central compartment. The population mean estimates for the clearance and volume of distribution at steady state were 26.4 L/h and 18.4 L, respectively. The pharmacokinetics were linear, with no dose-dependent or time-dependent effects on the clearance or volume of distribution, and with moderate interindividual variability. Covariate analyses showed that cardiac output significantly affected clearance, whereas patient age, bodyweight and renal function did not. Time delays between plasma concentrations and effect compartment concentrations, as described by the dissipation rate constant from the effect compartment, ranged from 0.32 h(-1) to 0.86 h(-1) for the different haemodynamic parameters of the final pharmacokinetic/pharmacodynamic model. A 50% recovery to pharmacodynamic baseline values was estimated to occur within 1 hour and a complete return to baseline was estimated to occur within 3-4 hours after the end of infusion. Intravenously administered cinaciguat had predictable pharmacokinetic and haemodynamic effects in patients with ADHF.