Contemporary Accounts in Drug Discovery and Development. Группа авторов

      3.6.2.4 Metabolism

      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. N‐glucuronidation is catalyzed predominantly by UGT1A9, as well as UGT1A1. CYP‐mediated metabolism is a minor clearance pathway (<5%).

      3.6.2.5 Elimination

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 HF 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 feces (primarily as vericiguat).

Table 3.7 Population pharmacokinetic model based steady‐state geometric mean (CV%) plasma pharmacokinetic parameters of vericiguat 2.5, 5, or 10 mg in heart failure patients (N = 2321).

PK parameters	2.5 mg	5 mg	10 mg
C max (μg/l)	120 (29.0)	201 (29.0)	350 (29.0)
AUC (μg•h/l)	2300 (33.9)	3850 (33.9)	6680 (33.9)

Figure 3.7 Pharmacokinetics of vericiguat in special populations.

      3.6.2.6 Special Populations

Based on a population pharmacokinetic analysis, age, gender, ethnicity, race, and baseline NT‐proBNP have not been identified as significant co‐variates and thus do not have a clinically meaningful effect on the PK of vericiguat in HFrEF patients. The effect of body weight on vericiguat exposure was not clinically meaningful. No clinically relevant increase in exposure was observed for subjects with mild hepatic impairment (Child‐Pugh A and B). The PK of vericiguat have not been studied in patients with severe hepatic impairment (Child‐Pugh C) (Figure 3.7).

      3.6.2.7 Drug Interactions

      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 and 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 PK of concurrently administered medications that are substrates of these enzymes or transporters.

      3.6.2.8 In vivo Assessment of Drug Interactions

       Effects of Other Drugs on the Pharmacokinetics of Vericiguat

The effects of coadministered drugs on the PK of vericiguat have been assessed in 10 clinical drug–drug interaction studies. Overall, there was no clinically relevant effect on vericiguat PK with coadministration of drugs increasing gastric pH (e.g. proton pump inhibitors, H2‐receptor antagonists, antacids) in HF patients; or with coadministration of mefenamic acid, ketoconazole, rifampicin, digoxin, warfarin, aspirin, sildenafil, or the combination of sacubitril/valsartan in healthy subjects [43]. There was no clinically relevant effect on vericiguat PK with coadministration of atazanavir based on physiologically based pharmacokinetic (PBPK) modeling. The results are summarized in Figure 3.8.

      These data indicate that no dose adjustment of vericiguat is recommended when coadministered with commonly prescribed medicinal products [44].

Figure 3.8 Effects of other drugs on the pharmacokinetics of vericiguat.

       Effects of Vericiguat on the Pharmacokinetics of Other Drugs

The effects of vericiguat on the PK of coadministered drugs have also been assessed in clinical drug–drug interaction studies [43, 45]: vericiguat had no clinically relevant effect on the PK of midazolam, digoxin, warfarin, sildenafil, and the combination of sacubitril/valsartan when coadministered in healthy subjects (Figure 3.9).

      3.6.3 Pharmacodynamic Interactions

      The effects of vericiguat on the PD of coadministered drugs have also been assessed in 6 clinical drug–drug interaction studies: vericiguat had no clinically relevant effect on the PD of aspirin, warfarin, sildenafil, and the combination of sacubitril/valsartan when coadministered in healthy subjects; or on the pharmacodynamics of organic nitrates when coadministered in patients with coronary artery disease [43, 45].

      3.6.4 Vericiguat Phase 2 and Phase 3 studies in HFrEF patients

      The transition from healthy volunteers to HFrEF patients investigated in SOCRATES‐REDUCED was supported by a modeling‐based bridging approach using clinical data from the sGC stimulators riociguat and nelociguat (BAY 60‐4552) replacing a standard proof‐of‐concept study and enabling a direct transition into Phase 2b [46].

Figure 3.9 Effects of vericiguat on the pharmacokinetics of other drugs [44].

The SOCRATES program was designed to study in two parallel dose‐ranging trials vericiguat at titrated dosing schemes up to 10 mg once per day in the highest target dose arm over 12 weeks in patients with stabilized worsening chronic HFrEF (SOCRATES‐REDUCED) and in patients with stabilized worsening chronic HFpEF (SOCRATES‐PRESERVED). Based on insights from the riociguat LEPHT study [25, 26, 46], patients with symptomatic worsening chronic HF were enrolled irrespective of documented elevations in pulmonary artery pressure. Since very high mortality and morbidity rates persist in patients who experience HF events despite receiving optimal medical therapy, these studies specifically enrolled patients within a one month window after a preceding HF hospitalization, or alternatively after a HF event that had to be treated with i.v. diuretics in an outpatient setting [47]. Rather than transient management with additional i.v. therapy, long‐term treatment with an oral sGC stimulator was deemed to carry promise [48] to meet this