Pharmacokinetics, Pharmacodynamics and Safety of a Single Dose of Imarikiren, a Novel Renin Inhibitor, in Healthy Male Subjects

Imarikiren hydrochloride (TAK‐272/SCO‐272) is a novel direct renin inhibitor with potential indications for cardiovascular and renal diseases. This phase I study evaluated the pharmacokinetics, pharmacodynamics and safety of a single oral administration of imarikiren in healthy Japanese male subjects. The Dose‐Ascending part (double‐blind, placebo‐controlled, parallel‐group design; n = 60) comprised six steps from 5 to 200 mg (n = 8 for imarikiren and n = 2 for placebo per step). The Food Effect part (n = 12) was an open‐label, 2 × 2 crossover design with a dose of 50 mg to evaluate the effect of food on the pharmacokinetics and safety of imarikiren. There was a generally linear relationship between dose and area under the plasma concentration–time curve (0 to infinity) or maximum plasma concentration of imarikiren. Food had no clinically significant effect on the exposure of imarikiren. Inhibition of plasma renin activity was rapid and lasted up to 24 hr at all doses. Plasma active renin concentration increased, reaching a maximum at approximately 6 hr, in a nearly dose‐dependent manner. Across both study parts, the number of subjects with treatment‐emergent adverse events ranged from 0 to 3 per group with no dependency on dose. All treatment‐emergent adverse events except two were mild in intensity; there were no serious adverse events or deaths. Single oral administration of imarikiren from 5 to 200 mg was safe and well tolerated. These findings suggest that further clinical development of a once‐daily imarikiren regimen is warranted.