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Metabolism and pharmacokinetic drug interaction profile of vericiguat, a soluble guanylate cyclase stimulator

Session Poster Session 3

Speaker Maximilian Lobmeyer

Event : Heart Failure 2019

  • Topic : heart failure
  • Sub-topic : Chronic Heart Failure: Pharmacotherapy
  • Session type : Poster Session

Authors : M Lobmeyer (Wuppertal,DE), M Gerisch (Wuppertal,DE), M-F Boettcher (Wuppertal,DE), D Thomas (Wuppertal,DE), M Gerrits (New Jersey,US), W Mueck (Wuppertal,DE), N Besche (Essen,DE), C Becker (Wuppertal,DE)

M Lobmeyer1 , M Gerisch2 , M-F Boettcher1 , D Thomas3 , M Gerrits4 , W Mueck1 , N Besche5 , C Becker1 , 1Bayer AG, Clinical Pharmacology - Wuppertal - Germany , 2Bayer AG, DMPK - Wuppertal - Germany , 3Bayer AG, Experimental Medicine - Wuppertal - Germany , 4Merck & Co., Inc., Kenilworth - New Jersey - United States of America , 5Chrestos Concept GmbH & Co. KG - Essen - Germany ,


Background/Introduction: Vericiguat is under investigation in patients with heart failure (HF; NCT02861534). This patient population is characterised by multiple comorbidities and concomitant medications.

Purpose: An understanding of the clearance mechanisms, elimination and potential for drug–drug interactions (DDIs) of vericiguat is a pre-requisite for dose recommendations.

Methods: Biotransformation of vericiguat was characterised in vitro using hepatocytes, liver microsomes, recombinant uridine diphosphate-glucuronosyltransferase (UGT) isoforms and with selective UGT inhibitors in liver microsomes. These were complemented by a human mass balance study with a single dose of 14C-labelled vericiguat 5 mg and six DDI studies in healthy volunteers (Table 1). The perpetrator DDI potential of vericiguat was investigated in vitro.

Clinically, the perpetrator DDI potential was assessed with the narrow-therapeutic index drugs digoxin and warfarin, and the cytochrome P450 (CYP) 3A4 index substrate midazolam. Vericiguat was administered as a victim drug with ketoconazole, rifampicin and mefenamic acid.

Results: After administration of 14C-labelled vericiguat, 53.1% and 45.2% of the dose was excreted via urine and faeces, respectively. The main metabolic pathway of vericiguat is glucuronidation via UGT1A9 and UGT1A1.

In vitro studies revealed that the risk of pharmacokinetic (PK) DDIs with substrates of CYP and UGT isoforms, as well as major transport proteins, is low. These were confirmed by the clinical studies (Figure 1).

Conclusion(s): A low PK interaction potential of vericiguat was estimated from in vitro data and confirmed in six studies. Maximum changes in vericiguat exposure (~30%) were within the range of overall PK vericiguat variability. These results indicate that the PK DDI profile of vericiguat is suited to the treatment of a HF population.

Table 1

Healthy volunteer study


Vericiguat treatment


Mass balance

Open-label, non-randomised, non-placebo-controlled

5 mg radiolabelled [14C] SD

Not applicable

DDI with warfarin

Randomised, double-blind, 2-fold crossover

10 mg OD for 9 days

Warfarin 25 mg SD

DDI with digoxin

Randomised, open-label, 2-fold crossover with additional fixed treatment period

10 mg OD for 10 days; 10 mg SD

Digoxin 0.375 mg OD for 14 days

DDI with CYP3A4 index substrate

Randomised, open-label, 2-fold crossover

10 mg OD for 4 days

Midazolam 7.5 mg SD

DDI with multi-pathway inhibitor

Randomised, open-label, 2-fold crossover

1.25 mg SD

Pre- and co-administration of ketoconazole 200 mg BID for 3 days

DDI with multi-pathway inducer

Non-randomised, open-label, fixed sequence

10 mg SD

Pre- and co-administration of rifampicin 600 mg OD for 9 days

DDI with UGT1A9 inhibitor

Randomised, open-label, 2-fold crossover

2.5 mg SD

Pre- and co-administration of mefenamic acid 500 mg followed by MDs of mefenamic acid 250 mg every 6 hours for 3 days

BID, twice-daily; CYP, cytochrome P450; DDI, drug–drug interaction; MD, multiple dose; OD, once-daily; SD, single dose; UGT uridine diphosphate-glucuronosyltransferase

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