Metabolism and Pharmacokinetic Drug–Drug Interaction Profile of Vericiguat, A Soluble Guanylate Cyclase Stimulator: Results From Preclinical and Phase I Healthy Volunteer Studies

Abstract

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.

The CNS-Penetrant Soluble Guanylate Cyclase Stimulator CY6463 Reveals its Therapeutic Potential in Neurodegenerative Diseases

“…For CY6463, the K p,uu was 0.86, indicating passive permeability across the blood-brain barrier in the rat without active efflux by transporters. For vericiguat, the K p,uu was indicating minimal partitioning into the CSF, likely due to efflux as vericiguat is a substrate for P-glycoprotein and breast cancer-resistance protein efflux transporters ( Boettcher et al, 2020 ). While these calculations do not represent the equilibrium at the steady state, CY6463 can be considered as being a fully CNS penetrant sGC stimulator, and vericiguat to have limited exposure in the CNS.…”

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

“…A summary of the PK sampling is provided in Table 1 of the Electronic Supplementary Material (ESM). The methodologies regarding the PK assessments of vericiguat have been previously described [ 23 , 24 ]. Method validation and analysis of the study samples were performed in accordance with the bioanalytical method validation guidance for industry of the US Food and Drug Administration [ 25 ].…”

Vericiguat: A Novel Oral Soluble Guanylate Cyclase Stimulator for the Treatment of Heart Failure

“…1,10 Vericiguat did not affect seated blood pressure in healthy patients when administered with sacubitril/valsartan. 1,8 Similarly, there was no significant difference in seated blood pressure when vericiguat was concomitantly administered with short- and long-acting nitrates in patients with coronary artery disease. 1 Vericiguat was well tolerated in patients with HF receiving short-acting nitrates; there is insufficient evidence for concomitant use of long-acting nitrates with vericiguat in this patient population.…”