Results of a phase I clinical trial of a new soluble guanylate cyclase stimulator in healthy volunteers

Introduction. Granik^® (the active substance is an indolinone derivative GRS) is a new domestic nitric oxide-independent stimulator of soluble guanylate cyclase (sGC). Stimulation of sGC represents a promising approach to the therapy of cardiovascular diseases caused by thrombosis, particularly in cases where traditional antiplatelet and anticoagulant agents are contraindicated and pose a high risk of bleeding. Granik^® has been in Phase I clinical trials, and this publication is devoted to the evaluation of its safety and pharmacokinetics in healthy volunteers.

Aim. The aim of the study was to evaluate the tolerability, safety and pharmacokinetics of Granik^® 20 mg capsules in healthy volunteers after administration under fasting conditions at doses of 20, 40, and 60 mg over a 7-day period.

Materials and methods. A double-blind, placebo-controlled study involved 48 healthy male volunteers who received Granik^® at doses of 20, 40, and 60 mg or placebo for 7 days. Tolerability was assessed as good, satisfactory, or unsatisfactory based on subjective data from the volunteers. Safety assessment was based on the analysis of adverse events, laboratory values, ECG data, and vital signs monitoring. GRS plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometric detection. Statistical analysis was performed using the R v.3.5 program (Revolution Analytics, USA) and parametric and nonparametric statistics depending on the nature of the data distribution.

Results and discussion. Granik^® at doses of 20, 40 and 60 mg demonstrated good tolerability and safety after 7-day administration to healthy volunteers (16 participants in 3 cohorts). Pharmacokinetic parameters varied significantly depending on the dose. The maximum plasma concentration (C_max) of the GRS compound was reached in 0.5–1.5 h. When Granik^® was administered at a dose of 60 mg, the GRS substance remained in plasma for a long time: the half-elimination period (t_1/2) was 24.61 ± 10.40 h. When Granik^® was administered at doses of 20 and 40 mg, elimination from plasma was accelerated: the half-elimination period decreased to 4.34 ± 3.61 h and 3.69 ± 5.09 h, respectively. The accumulation coefficient of the GRS substance did not statistically significantly differ when Granik^® was administered in the dose range of 20–60 mg per day.

Conclusion. Granik^® demonstrated good tolerability and a favorable safety profile when administered as a course. These results justify the transition to the next phase of clinical trials of Granik^®.

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