Pharmacokinetics and mass balance of vericiguat in rats and dogs and distribution in rats.

Vericiguat is a soluble guanylate cyclase stimulator. The pharmacokinetics, absorption, metabolism, and excretion properties of vericiguat in rats and dogs and the distribution in rats are reported. [14C]-labelled vericiguat was studied in intact and bile duct-cannulated rats (oral and intravenous administration), and dogs (oral administration).Vericiguat reached maximum plasma concentrations at 1-3 h after oral administration. Absolute bioavailability was moderate in rats and high in dogs. Vericiguat was the most abundant component in plasma of rats and dogs.After oral administration to rats, radioactivity was widely distributed. Penetration into the brain was minimal. Elimination was rapid from most tissues in rats. Most of the radioactivity was excreted in faeces (rat: 81%, dog: 89%), while low amounts were excreted in urine (rat: 11%, dog: 4%). Clearance routes in both species were unchanged excretion and metabolism via glucuronidation and oxidative reactions. After intravenous administration to bile duct-cannulated rats, a relevant proportion of the dose (30%) underwent direct excretion into the gastrointestinal tract as unchanged vericiguat.

Pharmacokinetics, excretion, distribution, and metabolism of 60-kDa polyethylene glycol used in BAY 94-9027 in rats and its value for human prediction.

The covalent binding of proteins with polyethylene glycol (PEG) molecules is a valuable tool to extend the half-life of many biotherapeutics, including factor VIII (FVIII) products to treat patients with haemophilia A. Although PEG has low toxicity, accumulation of large PEG molecules (>20-30 kDa) with long-term exposure is a potential concern. Thus, it is important to determine whether sufficient excretion processes exist for PEG molecules used in biotherapeutics. BAY 94-9027 is an extended-half-life FVIII product modified through addition of a 60-kDa (branched: dual 30-kDa) PEG molecule. BAY 1025662 is the 60-kDa PEG moiety used for PEGylation of BAY 94-9027. This study investigated the pharmacokinetic (PK) properties, distribution, and excretion of BAY 1025662 in rats in order to predict estimated 60-kDa PEG PK properties in patients. Plasma concentrations in male rats after a single 11-mg/kg intravenous dose of BAY 1025662 (approximating the cumulative PEG-60 exposure in patients during 30 years of BAY 94-9027 treatment) decreased with an initial half-life of 119 h (5 days) in the interval of 114-336 h post administration. Single-dose mass balance studies using radiolabeled BAY 1025662 ([prop-14C]BAY 1025662) showed that 30.4% of radioactivity was excreted within 1 week and 79.1% by Day 168 (primarily in urine). The terminal half-life of radioactivity elimination was approximately 24 days in blood and plasma and was 31-68 days in the majority of other organs up to Day 168. Elimination was nearly complete at the end of the experiment on Day 168; only ~4% of residual radioactivity was present in the animal body. There was no irreversible binding of radioactivity to any tissues and no penetration of the blood-brain barrier. Based on these results, very low steady-state concentrations of 60-kDa PEG were predicted in patients treated with BAY 94-9027, and the validity of these predictions was supported by clinical studies in which almost all 179 patients receiving BAY 94-9027 for prophylaxis had undetectable PEG in plasma for up to >5 years; those with detectable PEG levels demonstrated concentrations within the predicted range. These combined preclinical and clinical observations suggest that excretion processes are in place for high-molecular-weight PEGs such as the PEG-60 moiety used in BAY 94-9027.