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.

A Randomized, Single-Center, Double-Blind, Placebo-Controlled Multiple-Dose Phase 1 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Imarikiren in Healthy Adult Nonelderly and Elderly Male Subjects.

Imarikiren hydrochloride (TAK-272/ SCO-272) is a novel direct renin inhibitor. This randomized, double-blind, phase I study evaluated the safety and pharmacokinetics/pharmacodynamics of multiple oral administrations of imarikiren in healthy nonelderly (aged 20-45 years) and elderly (aged 65-85 years) Japanese male subjects. Subjects were randomized within 1 of 3 cohorts to receive imarikiren or placebo: Cohort 1 (imarikiren 80 mg; nonelderly), Cohort 2 (imarikiren 160 mg; nonelderly), or Cohort 3 (imarikiren 80 mg; elderly). Imarikiren or placebo was administered orally, once daily, for 7 days. Accumulation of imarikiren did not occur during the 7-day treatment period. Area under the plasma-concentration time curve and maximum plasma concentration of imarikiren were higher in elderly than in nonelderly subjects (52% and 39% higher, respectively). Inhibition of plasma renin activity was observed for 7 days and was maintained for at least 71 hours after the last imarikiren administration at the 80-mg (nonelderly and elderly) and 160-mg (nonelderly) doses. Plasma active renin concentration increased in nonelderly and elderly subjects; peak concentrations were higher on day 7 than on day 1. Increase from baseline in plasma active renin concentration was smaller in elderly than in nonelderly subjects during the 7-day treatment period and until 71 hours after last imarikiren administration. Treatment-emergent adverse events were reported in 33.3% (elderly) and 22.2% (nonelderly) of imarikiren subjects. Multiple oral administrations of imarikiren for 7 days were safe and well tolerated with no drug accumulation and strong and sustained suppression of plasma renin activity.