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

Figures

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  Fig. 1. Study design of the sacubitril/valsartan–vericiguat interaction study. Periods 1 and 2 were separated by a washout of 7–10 days. Unfilled and filled downward arrows indicate the start and end of coadministration, respectively. bid twice daily, qd once daily, SV sacubitril/valsartan

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  Fig. 2. Pharmacodynamic interactions—platelet aggregation. Data are expressed as means ± standard deviation. Treatments were vericiguat 15 mg, aspirin 500 mg, and vericiguat 15 mg plus aspirin 2 × 500 mg (500 mg administered qd for 2 days). a Impedance aggregometry, arachidonic acid; b impedance aggregometry, collagen-induced; both measured in units; and c turbidimetry, collagen-induced measured in percentages (PD analysis set, n = 13). Values below the LLOQ were substituted by half the LLOQ for the calculation of statistics. LLOQ lower limit of quantification, PD pharmacodynamic, qd once daily

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  Fig. 3. Point estimates, 90% CIs, and 95% prediction intervals for the ratio vericiguat plus warfarin/placebo plus warfarin of PD parameters and prothrombin INR. a Prothrombin time; b factor VII activity; c factor II activity; d factor X activity; and e INR by treatment. The shaded boxes represent the IQR (25th–75th percentiles). The line inside the box represents the median, and the rhombus inside the box represents the arithmetic mean. Whiskers represent the maximum value below 1.5*IQR above the 75th percentile and the minimum value above 1.5*IQR below the 25th percentile. Symbols outside the whiskers represent outliers. CIs confidence intervals, INR international normalized ratio, IQR interquartile range, PD pharmacodynamic, IQR interquartile range, AUC96 area under the concentration–time curve from time zero to 96 h after dosing

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  Fig. 4. Geometric mean/standard deviation for concentrations of drugs in plasma (n = 23). Mean plasma concentration profile of a R-warfarin, b S-warfarin, and c vericiguat. Square symbols represent vericiguat plus warfarin; circular symbols represent placebo plus warfarin (a, b). Square symbols represent profile day 5; circular symbols represent profile day 6 (c)