Pharmacokinetics, Pharmacodynamics, and Tolerability of ACT-077825, a New Direct Renin Inhibitor After Multiple-ascending Doses in Healthy Subjects

Abstract

This study was conducted to characterize the multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-077825, a new direct renin inhibitor, in healthy male subjects. In this single-center, double-blind, placebo-controlled, active-controlled (20 mg of enalapril), randomized multiple-ascending dose study, ACT-077825 was administered once a day. for 7 days in the 50-1000 mg dose range to sodium- and potassium-restricted subjects. ACT-077825 pharmacokinetics on days 1 and 7 were characterized by dose-proportional increases in Cmax and AUCτ. At steady state, accumulation was modest (1.5- to 1.7-fold). Enalapril caused an increase in plasma active renin concentration and plasma renin activity (PRA). ACT-077825 dose dependently increased active renin on days 1 and 7 and inhibited PRA dose dependently only on day 1. On day 7, the maximal PRA inhibition was attained after 250 mg of ACT-077825. In contrast to enalapril, ACT-077825 did not induce any consistent lowering effect on blood pressure when compared with placebo. Of the reported adverse events, diarrhea, headache, and postural dizziness were more frequent. The incidence of diarrhea was greater in the 1000-mg group and a dose of 500 mg of ACT-077825 was identified as the maximum tolerated dose. Overall, pharmacokinetic, pharmacodynamic, and tolerability profiles warrant the further investigation of ACT-077825 in patients with hypertension.

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

“…The pharmacokinetic parameters determined in these healthy populations were in agreement with the previous pharmacokinetic investigations performed in healthy male subjects following escalating single oral doses (from 1 to 1,000 mg) of ACT-0775825 [6] as well as after repetitive administration of escalating doses during 7 days [9], confirming that the exposure (C max and AUC) of ACT-077825 was dose proportional for single doses ranging from 100 to 1,000 mg [6]. Furthermore, as previously reported [6], a double peak for C max was observed in all groups independently of age and sex, suggesting the presence of enterohepatic recycling of ACT-077825.…”

“…The metabolic clearance of propranolol, a β-blocker substrate of CYP2D6, was significantly lower in females, leading to a 70% higher exposure [18]. It has been shown that ACT-077825 is a substrate of CYP3A4 [9,19] and it was reported that the clearance of many CYP3A substrates may be reduced with age, but no sex-related differences in clearance have been reported for these drugs [20]. However, the exposure to nefazodone, a substrate and inhibitor of CYP3A4, is 50% higher in elderly women compared to young subjects or elderly men [21].…”

“…Concentrations of ACT-077825 in plasma were determined using a validated LC-MS/MS assay, whose limit of quantification (LOQ) was 1.0 ng/ml [9]. Concentrations were calculated by interpolation from a calibration curve.…”

“…The oral bioavailability of ACT-077825 reached up to 30% in rats and 12% in cynomolgus monkeys at doses of 10 and 30 mg/kg, respectively [6]. Single and multiple ascending dose studies in healthy human subjects over 7 days have shown that ACT-077825 was well tolerated up to 500 mg [6,9]. …”

Novel RAAS agonists and antagonists: clinical applications and controversies

“…In 2013, a new DRI, ACT-077825, was shown to have an adequate safety profile in humans when administered once daily. 103 ACT-077825 inhibits plasma renin activity, while the levels of immunoreactive renin increase, a pattern typical of DRIs. 102 However, the decrease in plasma renin activity is transient and is not dose-dependent at 7 days.…”