RESPONSES TO AN ORALLY-ACTIVE RENIN INHIBITOR, REMIKIREN (RO-42-5892), AFTER CONTROLLED SALT DEPLETION IN HUMANS

The biological effects of dose-dependent inhibition of renin have rarely been extensively studied after oral (p.o.) dosing in humans. We studied remikiren (Ro42-4892), a selective renin inhibitor, in normal volunteers after activation of the renin-angiotensin system (RAS) based on salt depletion. Twelve normal men (28 +/- 9 years, 77 +/- 10 kg), comprising three consecutive dose panels of 4 subjects, received four treatments, double-blind and randomised 2 weeks apart: panel I, placebo (P), or 30, 100, and 300 mg, remikiren; panel II, placebo or 300, 600 mg, 1,000; panel III, placebo or 30, 600, and 1,000 mg. The RAS was activated by 40 mmol/day sodium diet plus frusemide (40 mg BDS), for 3 days before each study day. Data (mean +/- SD) were examined by repeated-measures analysis of variance (ANOVA). RAS activation was confirmed by 24-h urinary sodium excretion (screen, 142 +/- 74 mmol/24 h; prestudy, 66 +/- 33, 59 +/- 41, 78 +/- 4, 73 +/- 30 mmol/24 h) and increase in plasma renin activity (PRA) (screen, 0.8 +/- 0.3 ng AI/ml/h; before dosing, P, 6.5 +/- 3.1; 30 mg, 8.2 +/- 3; 100 mg, 9.4 +/- 5.7; 300 mg, 6.5 +/- 2.4; 600 mg, 5.2 +/- 2; 1,000 mg, 6.2 +/- 4.4 ng AI/ml/h). PRA was reduced in dose dependently (mean minimal activity: 30 mg 1.4 +/- 1.2; 100 mg, 1.6 +/- 1; 300 mg, 0.1 +/- 0.1, 600 mg, 0.1 +/- 0.1; 1,000 mg, 0.01 +/- 0.02), and active renin was increased (mean maximal active renin; 30 mg, 182 +/- 186; 100 mg, 185 +/- 83; 300 mg, 252 +/- 240; 600 mg, 262 +/- 100, 1,000 mg, 1,417 +/- 2,008 pg/ml). Maximal effects were noted soon after dosing for PRA (30 mg, 1.1 +/- 0.3; 100 mg, 1 +/- 0; 300 mg, 1 +/- 0; 600 mg, 1.3 +/- 0.4; 1,000 mg, 1.3 +/- 0.4 h) but slower for increase in active renin (30 mg, 4.6 +/- 1.3, 100 mg, 3 +/- 1.4; 300 mg, 1.8 +/- 1.6; 600 mg, 2.8 +/- 1.5; 1,000 mg, 3.4 +/- 1.4 h). Despite evidence of biochemical effect, supine blood pressure (BP) was not significantly affected by active treatment. Erect BP did show a significant decrease from pretreatment values, but only after 1,000 mg remikiren 1 h after dosing (P, baseline, 116 +/- 12/68 +/- 7; 1 h, 112 +/- 8/65 +/- 7; 1,000 mg, baseline, 114 +/- 12/65 +/- 7; 1 h, 96 +/- 9/50 +/- 18). Drug concentrations showed a wide dose-related spectrum of mean maximal concentrations (30 mg, 1.07 +/- 1.64; 100 mg, 2.17 +/- 1.38; 300 mg, 28.88 +/- 16.95; 600 mg, 67.76 +/- 36.06; 1,000 mg, 136.9 +/- 156 ng/ml). Values for T-max were generally observed soon after dosing and were not clearly dose related (30 mg, 0.5 +/- 0.5; 100 mg, 0.56 +/- 0.77; 300 mg, 0.66 +/- 0.51; 600 mg, 0.44 +/- 0.11; 1,000 mg, 0.94 +/- 0.63 h). Remikiren is enzymatically active after p.o. administration in humans in a dose-dependent manner. Only the dose of 1,000 mg reduced BP in salt-deplete subjects. Haemodynamic effects are therefore demonstrable but are slight, dissociated from RAS inhibition in blood, despite confirmed activation of the RAS. BP changes parallel the pharmacokinetic profile. The latter is unlikely to permit once daily dosing with 24-h effect. Higher doses and or controlled-release p.o. formulations or alternative routes of administration would be required to achieve antihypertensive efficacy. Owing to the selective nature of renin inhibition, a separate profile of efficacy and response in hypertensive patients is unlikely.