Single-Dose Pharmacokinetics of the Renin Inhibitor ACT-077825 in Elderly and Young Subjects of Both Sexes

Abstract

Background/Aims: The study objective was to investigate and compare the pharmacokinetics of a single oral dose of ACT-077825, a novel direct renin inhibitor, in young and elderly, male and female healthy subjects and to evaluate the safety and tolerability of ACT-077825 in these population groups. Methods: A total of 32 healthy subjects were included in this single-center, open-label study. The subjects were divided into 4 groups, including 8 young male, 8 young female, 8 elderly male and 8 elderly female subjects. Each participant received a single 200-mg dose of ACT-077825. Blood samples were taken over 5 days (120 h) to determine the plasma levels of ACT-077825. Safety and tolerability were monitored using standard assessments before drug administration, on the administration day and at the end of the blood sampling period. Results: Upon pooling male and female subjects, exposure was higher in elderly compared to young subjects, showing an increase of 65% for AUC_0-_∞, 40% for C_max and 38% for t_1/2. While young male and female subjects showed similar plasma profiles and exposure, a significant increase in exposure occurred with age in both sexes compared to younger subjects. The difference was largest between young and elderly females. Furthermore, the exposure to ACT-077825 was around 30% higher in elderly female compared to elderly male subjects. ACT-077825 was well tolerated by all groups, including the elderly females who showed the highest exposure. Conclusions: ACT-077825 exposure is moderately increased in elderly subjects. The clinical relevance of this observation should be explored in the context of further studies.

Signaling pathways in vascular function and hypertension: molecular mechanisms and therapeutic interventions

“…ACT 178882, the next generation of ACT-077825, is still under exploration. 532,533 The mineralocorticoid receptor antagonist mainly refers to spironolactone, eplerenone, and canrenone. As a potassium-sparing diuretic, the efficacy of spironolactone to treat hypertension has been confirmed by RCTs.…”