Age and Sex Effects on the Single‐ and Multiple‐Dose Safety and Pharmacokinetics of the New Renin Inhibitor ACT‐178882

AIM: To investigate the effect of age and sex on the single- and multiple-dose safety and pharmacokinetics of ACT-178882, a new direct renin inhibitor. METHODS: In the single-dose, open-label part of the study, healthy young and elderly male and female subjects received a dose of 300 mg ACT-178882. In the multiple-dose, double-blind, placebo-controlled part of the study, healthy elderly male and female subjects received ACT-178882 (300 or 600 mg) or placebo once-a-day for 14 days. RESULTS: Mild headache and diarrhea were the most common adverse events in the single- and multiple-dose parts, respectively. The frequency of diarrhea increased dose dependently, and no placebo subjects reported this adverse event. Administration of ACT-178882 did not result in any clinically relevant changes in ECG, vial signs, clinical laboratory, body weight, or physical examination. In the single-dose part and independent of sex, values for Cmax and AUC0-∞ were about 85% higher in elderly compared with young subjects, and t1/2 was about 5 h longer (29.3 vs. 24.1 h). In both age groups, plasma ACT-178882 concentrations were slightly higher in female versus male subjects. Following multiple-dose administration to elderly subjects, accumulation of ACT-178882 was moderate, about 1.8-fold, t1/2 was unchanged as compared with single-dose administration, sex effects were minimal, and the increase in the exposure with increasing dose appeared less than dose proportional. CONCLUSION: Overall, single- and multiple-dose administration of ACT-178882 was well tolerated. No dose adaptation based on sex is necessary, whereas a dose reduction based on age could be considered.