BACKGROUND: Vericiguat is a stimulator of soluble guanylate cyclase currently 
under investigation as a first-in-class therapy for worsening chronic heart 
failure (NCT02861534). Patients with heart failure often require polypharmacy 
because of comorbidities. Hence, understanding the clearance mechanisms, 
elimination, and potential for pharmacokinetic drug-drug interactions of 
vericiguat is important for dose recommendations in this patient population.
METHODS: Biotransformation and perpetrator properties of vericiguat were 
characterized in vitro using human hepatocytes, liver microsomes, and 
recombinant enzymes. This was complemented by a human mass balance study and ten 
drug-drug interaction studies in healthy volunteers wherein vericiguat was 
co-administered orally with omeprazole, magnesium/aluminum hydroxide, 
ketoconazole, rifampicin, mefenamic acid, midazolam, warfarin, digoxin, 
sacubitril/valsartan, aspirin, or sildenafil.
RESULTS: In the human mass balance study, mean total radioactivity recovered was 
98.3% of the dose administered (53.1% and 45.2% excreted via urine and feces, 
respectively). The main metabolic pathway of vericiguat is glucuronidation via 
uridine diphosphate-glucuronosyltransferase 1A9 and 1A1. In vitro studies 
revealed a low risk of vericiguat acting as a perpetrator by inhibiting 
cytochrome P450s, uridine diphosphate-glucuronosyltransferase isoforms, or major 
transport proteins, or by inducing cytochrome P450s. These observations were 
supported by phase I drug-drug interaction studies. Phase I studies that 
assessed the propensity of vericiguat as a victim drug showed changes in the 
range that did not warrant recommendations for dose adjustment in phase III.
CONCLUSIONS: A low pharmacokinetic interaction potential of vericiguat was 
estimated from in vitro data and confirmed in vivo. Thus, vericiguat is suitable 
for a patient population with multiple comorbidities requiring polypharmacy.