Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42-5892) in hypertensive patients.
1 Three double-blind, randomized, placebo controlled, multiple oral dose studies in patients with mild to moderate hypertension were performed to study tolerability, pharmacodynamics and pharmacokinetics of remikiren. Doses of 100-800 mg remikiren or placebo were given over 8 days to altogether 144 patient volunteers. In some cases (n = 46) single i.v. doses of 100 mg were administered 4 h after the last oral dose. Plasma remikiren concentrations, plasma renin activity and immunoreactive renin concentrations were measured. Pharmacokinetic parameters were estimated using model independent techniques and the concentration-effect relationship was evaluated using population pharmacometric methods. 2 In most patients no distinct absorption and disposition phase could be identified, since plasma concentrations fluctuated widely over a period of approximately 10 h. Peak plasma concentrations (Cmax) were achieved within 0.25-2 h postdose. Mean Cmax values (on the first and last day of oral treatment) were in the magnitude of 4-6 ng ml(-1) (200 mg), 23-27 ng ml(-1) (300 mg), 65-83 ng ml(-1) (600 mg) and 47-48 ng ml(-1) (800 mg). Cmax and AUC0-t values were clearly different for different doses within single studies. Intersubject variability in pharmacokinetic parameters was much higher than intrasubject variability. No drug accumulation in plasma was apparent. 3 Inhibition of the angiotensin I production rate correlated well with plasma drug concentrations according to the Emax-model. An IC50 value of 0.5 ng ml(-1) (0.8 nM) was estimated. No correlation between blood pressure changes on the last day of oral treatment and either plasma remikiren concentrations or plasma renin inhibition was found.
Weber
C
C
F. Hoffmann-La Roche Ltd, Clinical Research and Development, CH-4002 Basel, Switzerland.
Birnböck
H
H
Leube
J
J
Kobrin
I
I
Kleinbloesem
C H
CH
Van Brummelen
P
P
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000803:Angiotensin I / Q000037:antagonists & inhibitors; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D000092502:Renin Inhibitors
D000803:Angiotensin I; D007093:Imidazoles; D000092502:Renin Inhibitors; C065581:remikiren