Dataset Information

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.

SUBMITTER: Boettcher M

PROVIDER: S-EPMC7658073 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Boettcher Michael M Gerisch Michael M Lobmeyer Maximilian M Besche Nina N Thomas Dirk D Gerrits Mireille M Lemmen Julia J Mueck Wolfgang W Radtke Martin M Becker Corina C

Clinical pharmacokinetics 20201101 11

<h4>Background</h4>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.<h4>Methods</h4>Biotransformation and p ...[more]

PMID: 32458378

Similar Datasets

Project description:Background: Lower-limb peripheral artery disease (PAD) is one of the major complications of diabetes mellitus. PAD is associated with poor limb and cardiovascular prognoses, along with a dramatic decrease in life expectancy. Despite major medical advances in the treatment of diabetes, a substantial therapeutic gap remains in the PAD population. Praliciguat is an orally available soluble guanylate cyclase (sGC) stimulator that has been reported both pre-clinically and in early-stage clinical trials to have favorable effects in metabolic and hemodynamic outcomes, suggesting that it may have a potential beneficial effect in PAD. Objective: We evaluated the effect of praliciguat on hind limb ischemia (HLI) recovery in a mouse model of type 2 diabetes. Methods: HLI was induced in leptin receptor-deficient (Leprdb/db) mice by ligation and excision of the left femoral artery. Praliciguat (10 mg/kg/day) was administered in the diet starting 3 days before surgery. Results: 28 days after surgery, ischemic foot perfusion and function parameters were better in praliciguat-treated mice than in vehicle controls. Improved ischemic foot perfusion was not associated with either improved traditional cardiovascular risk factors (i.e., weight, glycemia) or increased angiogenesis. However, treatment with praliciguat significantly increased arteriole diameter, decreased intercellular adhesion molecule 1 (ICAM1) expression, and prevented the accumulation of oxidative pro-angiogenic and pro-inflammatory muscle fibers. While investigating the mechanism underlying the beneficial effects of praliciguat therapy, we found that praliciguat significantly downregulated Myh2 and Cxcl12 mRNA expression in cultured myoblasts and that conditioned medium form praliciguat-treated myoblast decreased ICAM-1 mRNA expression in endothelial cells. These results suggest that praliciguat therapy may decrease ICAM-1 expression in endothelial cells by downregulating Cxcl12 in myocytes. Conclusion: Our results demonstrated that praliciguat promotes blood flow recovery in the ischemic muscle of mice with type 2 diabetes, at least in part by increasing arteriole diameter and by downregulating ICAM-1 expression.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure