Article date: December 1993
By: CORNELIA WEBER, HERBERT BIRNBÖCK, JOACHIM LEUBE, ISAAC KOBRIN, CORNELIS H. KLEINBLOESEM, PETER BRUMMELEN, in Volume 36, Issue 6, pages 547-554
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 immuno‐reactive renin concentrations were measured. Pharmacokinetic parameters were estimated using model independent techniques and the concentration‐effect relationship was evaluated using population pharmacometric methods.
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 AUCO‐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.
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 N) 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.
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 immuno‐reactive renin concentrations were measured. Pharmacokinetic parameters were estimated using model independent techniques and the concentration‐effect relationship was evaluated using population pharmacometric methods.
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 AUCO‐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.
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 N) 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.
DOI: 10.1111/j.1365-2125.1993.tb00413.x
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