Chemical formula: C₁₉H₁₆F₂N₈O₂ Molecular mass: 426.388 g/mol
Vericiguat is a stimulator of soluble guanylate cyclase (sGC). Heart failure is associated with impaired synthesis of nitric oxide (NO) and decreased activity of its receptor, sGC. Deficiency in sGC-derived cyclic guanosine monophosphate (cGMP) contributes to myocardial and vascular dysfunction. Vericiguat restores the relative deficiency in the NO-sGC-cGMP signalling pathway by directly stimulating sGC, independently of and synergistically with NO, to augment the levels of intracellular cGMP, which may improve both myocardial and vascular function.
The pharmacodynamic effects of vericiguat are consistent with the mode of action of a sGC stimulator resulting in smooth muscle relaxation and vasodilation.
In a 12-week placebo-controlled dose-finding study (SOCRATES-REDUCED) in patients with heart failure, vericiguat demonstrated a dose-dependent reduction in NT-proBNP, a biomarker in heart failure, compared to placebo when added to standard of care. In VICTORIA, the estimated reduction from baseline NT-proBNP at week 32 was greater in patients who received vericiguat compared with placebo.
In a dedicated QT study in patients with stable coronary artery disease, administration of 10 mg of vericiguat at steady state did not prolong the QT interval to a clinically relevant extent, i.e. the maximum mean prolongation of the QTcF interval did not exceed 6 ms (upper bound of the 90% CI <10 ms).
Vericiguat shows time-independent pharmacokinetics with low to moderate variability when administered with food. Pharmacokinetics are dose proportional in healthy volunteers and slightly less than dose proportional in heart failure patients. Vericiguat accumulates in plasma up to 155-171% and reaches pharmacokinetic steady state after approximately 6 days. The mean steady-state population pharmacokinetic parameters of vericiguat in heart failure patients are summarised in the table below. Steadystate exposure is estimated to be about 20% higher in heart failure patients when compared to healthy volunteers.
Population pharmacokinetic model based steady-state geometric mean (CV%) plasma pharmacokinetic (PK) parameters of 2.5 mg, 5 mg, or 10 mg vericiguat in heart failure patients (N=2,321):
| PK Parameters | 2.5 mg | 5 mg | 10 mg |
|---|---|---|---|
| Cmax (µg/L) | 120 (29.0) | 201 (29.0) | 350 (29.0) |
| AUC (µg•h/L) | 2,300 (33.9) | 3,850 (33.9) | 6,680 (33.9) |
The absolute bioavailability of vericiguat is high (93%) when taken with food. Bioavailability (AUC) and peak plasma levels (Cmax) of vericiguat administered orally as a crushed tablet in water are comparable to that of a whole tablet.
Administration of vericiguat with a high-fat, high-calorie meal increases Tmax from about 1 hour (fasted) to about 4 hours (fed), reduces PK variability, and increases vericiguat exposure by 19% (AUC) and 9% (Cmax) for the 5 mg tablet and by 44% (AUC) and 41% (Cmax) for the 10 mg tablet as compared with the fasted state. Similar results were obtained when vericiguat was administered with a low-fat, high-carbohydrate meal. Therefore, vericiguat should be taken with food.
The mean steady-state volume of distribution of vericiguat in healthy subjects is approximately 44 L. Plasma protein binding of vericiguat is about 98%, with serum albumin being the main binding component. Plasma protein binding of vericiguat is not altered by renal or hepatic impairment.
Glucuronidation is the major biotransformation pathway of vericiguat to form an N-glucuronide, which is pharmacologically inactive and the major drug-related component in plasma, accounting for 72% of the total drug-related AUC, with the parent vericiguat accounting for 28% of the total drugrelated AUC. N-glucuronidation is catalysed predominantly by UGT1A9, as well as UGT1A1. CYP-mediated metabolism is a minor clearance pathway (<5%).
The potential effect of UGT-related genetic polymorphism has not been investigated given the low-tomoderate inter-individual variability of vericiguat (see table). Titration of vericiguat mitigates the clinical impact of potential changes in exposure.
Vericiguat is a low-clearance drug (1.6 L/h in healthy subjects). The half-life is about 20 hours in healthy subjects and 30 hours in heart failure patients. Following oral administration of [14C]-vericiguat to healthy subjects, approximately 53% of the dose was excreted in urine (primarily as the N-glucuronide), and 45% of the dose was excreted in faeces (primarily as vericiguat, likely due to excretion of the N-glucuronide into bile followed by hydrolysis back to vericiguat by intestinal microflora).
In patients with heart failure with mild, moderate, and severe renal impairment not requiring dialysis, the mean exposure (AUC) of vericiguat was increased by 5%, 13%, and 20% respectively, compared to patients with normal renal function. These differences in exposure are not considered clinically relevant. The pharmacokinetics of vericiguat have not been studied in patients with eGFR <15 mL/min/1.73 m² at treatment initiation or on dialysis.
In a dedicated clinical pharmacology study, otherwise healthy participants with mild, moderate, and severe renal impairment, had 8%, 73%, and 143% respectively, higher mean vericiguat exposure (unbound AUC normalised for body weight) after a single dose compared to healthy controls. The apparent discrepancy of the effect of renal impairment on vericiguat exposure between the dedicated clinical pharmacology study and the analysis in patients with heart failure may be attributed to differences in study design and size.
No relevant increase in exposure (unbound AUC) was observed for subjects with mild hepatic impairment (Child-Pugh A) with mean exposure to vericiguat 21% higher compared to healthy subjects with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh B), mean exposure to vericiguat was approximately 47% higher compared to their healthy subjects with normal hepatic function. The pharmacokinetics of vericiguat have not been studied in patients with severe hepatic impairment (Child-Pugh C).
Based on an integrated population pharmacokinetic analysis of vericiguat in patients with heart failure, age (23-98 years), body weight, gender, ethnicity, race and baseline NT-proBNP do not have a clinically meaningful effect on the pharmacokinetics of vericiguat.
No studies with vericiguat have been performed yet in paediatric patients.
Vericiguat is a substrate for UGT1A9, as well as UGT1A1. In vitro studies indicate that vericiguat and its N-glucuronide are neither inhibitors of major CYP isoforms (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) or UGT isoforms (UGT1A1, 1A4, 1A6, 1A9, 2B4, and 2B7), nor inducers of CYP1A2, 2B6 and 3A4, at clinically relevant concentrations.
Vericiguat is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters and is not a substrate of organic cation transporter (OCT1) or organic anion transporting polypeptides (OATP1B1, OATP1B3). Vericiguat and its N-glucuronide are not inhibitors of drug transporters, including P-gp, BCRP, BSEP, OATP1B1/1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2K, at clinically relevant concentrations.
Overall, these data indicate that the administration of vericiguat is unlikely to affect the pharmacokinetics of concurrently administered medicinal products that are substrates of these enzymes or transporters.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and male and female fertility.
In repeat-dose toxicity studies, the toxicological profile was characterised by effects secondary to exaggerated pharmacodynamics. Secondary to smooth muscle relaxation haemodynamic and gastrointestinal effects were noted in all species investigated. In adolescent rapidly-growing rats, reversible bone effects consisting of hypertrophy of growth plate and hyperostosis and remodelling of metaphyseal and diaphyseal bone were seen. These effects were not observed after chronic administration of vericiguat to adult rats and almost full-grown dogs.
A study in pregnant rats showed that vericiguat is transferred to the foetus through the placenta. Developmental toxicity studies in rats with vericiguat administered orally during organogenesis showed no developmental toxicity up to at least 21 times the human exposure (based on unbound AUC) at the maximum recommended human dose (MRHD) of 10 mg. In rabbits, late abortions and resorptions were observed, at maternally toxic doses at ≥6 times the human exposure at the MRHD. In a pre-/postnatal toxicity study in rats, at maternal toxic doses decreased pup body weight gain resulting in a slight delay in incisor eruption and a slight delay in vaginal opening was observed at approximately ≥21 times the human exposure at the MRHD. An increased incidence of stillbirths and decreased pup survival and a delay in balano-preputial separation were observed at 49 times the human exposure at the MRHD.
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