Pharmacodynamic and Pharmacokinetic Interaction Profile of Vericiguat: Results from Three Randomized Phase I Studies in Healthy Volunteers.

BACKGROUND: Vericiguat, a direct stimulator of soluble guanylate cyclase, has been developed as a first-in-class therapy for symptomatic chronic heart failure (HF) and ejection fraction < 45%.

METHODS: Safety, pharmacodynamic (PD), and pharmacokinetic (PK) interactions between vericiguat and drugs used in HF (sacubitril/valsartan [SV] and aspirin [acetylsalicylic acid]) or with a narrow therapeutic index (warfarin) were evaluated in three phase I studies.

RESULTS: Vericiguat 15 mg (single dose [SD]) had no effect on bleeding time or platelet aggregation when coadministered with aspirin 1000 mg versus aspirin alone: estimated differences in least squares means 2.7% (95% confidence interval [CI] - 90.4 to 95.8) and 2.4% (95% CI - 7.0 to 11.8) turbidimetry, respectively. Vericiguat 10 mg (once daily) had no effect on coagulation inhibition elicited by warfarin 25 mg (SD; mean ratios of area under the concentration-time curve from time zero to 96 h for clotting parameter treatment comparisons approximated 100.0%). There were no clinically relevant PD changes whether SV 97/103 mg was administered with single or multiple doses of vericiguat 2.5 mg or placebo (differences in systolic blood pressure [BP] - 1.66 mmHg [90% CI - 4.22 to 0.90]; diastolic BP - 1.80 mmHg [90% CI - 3.24 to - 0.36]; heart rate - 0.33 beats/min [90% CI - 2.25 to 1.60]). Vericiguat demonstrated no PK interactions when coadministered with aspirin, warfarin, or SV at steady state. Treatments were well tolerated.

CONCLUSIONS: Coadministration of vericiguat with SV, aspirin, or warfarin was well tolerated. No clinically relevant PD or PK interactions were observed, supporting concomitant use of these drugs, commonly used by patients with HF, with vericiguat and no dose adjustment.

EUDRACT NUMBER: 2014-000765-52; 2014-004880-19; 2015-004809-16.