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

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ORIGINAL RESEARCH ARTICLE

Pharmacodynamic and Pharmacokinetic Interaction Profile of Vericiguat: Results from Three Randomized Phase I Studies in Healthy Volunteers Michael Boettcher1 · Stephanie Loewen2 · Mireille Gerrits3 · Corina Becker1

© The Author(s) 2020

Abstract 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  120 ms or a QTc interval > 450 ms; systolic blood pressure (SBP)  145 mmHg; diastolic blood pressure (DBP)  95 mmHg (only DBP > 95 mmHg for the aspirin study); and heart rate (HR)  90 beats/min. Owing to safety reasons and the combination of two cardioactive drugs in the SV study, the exclusion criteria included a QRS complex interval of > 100 ms. Concomitant medication use other than the study drug was not permitted without informing the study investigator. Participants gave written informed consent to participate before entering the studies. Studies were conducted in accordance with the currently accepted version of the Declaration of Helsinki—the International Conference on Harmonisation Good Clinical Practice Guideline. All protocol and protocol amendments were reviewed by each study site’s Independent Ethics Committee (IEC) or Institutional Review Board (IRB) and approved under the leadership of the IEC/IRB of the coordinating investigator (EthikKommission der Aerztekammer Nordrhein, Duesseldorf, Germany) before the start of the study.

2 Methods

2.2.1 Aspirin Interaction Study

2.1 Study Population

This open-label study consisted of two parts: a pilot part, in which subjects received a single dose (SD) of vericiguat 15  mg (3 × 5  mg immediate-release [IR] tablets); and a three-period, crossover main part, in which subjects received three treatments: [(A) vericiguat 15 mg on day 1; (B): aspirin 500 mg on day –1 and day 1; and (C): aspirin 500 mg on day –1 and vericiguat 15 mg concomitantly with aspirin 500 mg on day 1)] in randomized sequence order with a washout

Healthy male volunteers with a body mass index (BMI) of 18.0–30.0 kg/m2 and aged 18–45 or 18–55 years were eligible for participation in the aspirin and warfarin studies, respectively. Male subjects with a BMI of 18.0–29.9 and aged 40–60 years were eligible for participation in the SV study. A total of 15, 29, and 32 subjects were randomized

2.2 Study Designs, Assessments, and Analysis All three studies were randomized, single-center studies. Individual study designs and treatment groups are shown in Table 1. In the aspirin study, vericiguat was administered in the fasted state due to analytical reasons involving interferences with clotting parameters, and, due to the effects of food [18], 15 mg was selected such that vericiguat plasma levels would approximate those following administration of 10 mg (fed). In the warfarin study, vericiguat 10 mg once daily was evaluated, as this would have reached steady state by day 6 (warfarin coadministration). In the SV study, vericiguat 2.5 mg was eval