Pharmacokinetic and dynamic interactions of the angiotensin-converting enzyme inhibitor imidapril with hydrochlorothiazide, bisoprolol and nilvadipine

• Published in: European journal of clinical pharmacology 2001-07, Vol.57 (4), p.275-284
• Main Authors: BREITHAUPT-GRÖGLER, K, UNGETHÜM, W, MEURER-WITT, B, BELZ, G. G
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - pharmacokinetics; Adrenergic beta-Antagonists - pharmacology; Adult; Angiotensin-Converting Enzyme Inhibitors - pharmacokinetics; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Antihypertensive agents; Antihypertensive Agents - pharmacokinetics; Antihypertensive Agents - pharmacology; Area Under Curve; Biological and medical sciences; Bisoprolol - pharmacokinetics; Bisoprolol - pharmacology; Calcium Channel Blockers - pharmacokinetics; Calcium Channel Blockers - pharmacology; Cardiovascular system; Clinical trials; Confidence intervals; Cross-Over Studies; Diuretics; Double-Blind Method; Drug Interactions; Drug therapy; Hemodynamics - drug effects; Humans; Hydrochlorothiazide - pharmacokinetics; Hydrochlorothiazide - pharmacology; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Imidazolidines; Male; Medical sciences; Nifedipine - analogs & derivatives; Nifedipine - pharmacokinetics; Nifedipine - pharmacology; Pharmacology. Drug treatments; Sodium Chloride Symporter Inhibitors - pharmacokinetics; Sodium Chloride Symporter Inhibitors - pharmacology
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s002280100323

The pharmacokinetic and dynamic interactions of the angiotensin-converting enzyme (ACE) inhibitor imidapril with other therapeutic principles used in hypertension and heart failure were evaluated. In three separate, double-blind, placebo-controlled, four-way cross-over studies in healthy volunteers (n = 16 each), single oral doses of imidapril 10 mg (I), hydrochlorothiazide 12.5 mg (H), bisoprolol 5 mg (B) and nilvadipine 8 mg (N) were administered as monotherapies, and in IH, IB and IN combinations. Plasma concentrations of imidaprilat and H were followed up to 48 h, those of B and N up to 24 h and area under the concentration time curve (AUC), maximum plasma concentration (Cmax) and time to Cmax (tmax) were determined. Blood pressure (BP), heart rate (HR) and non-invasive haemodynamics [total peripheral resistance (TPR, N and H), systolic time intervals (STI, N and H), and plasma renin activity (PRA)] were assessed up to 24 h. There were no pharmacokinetic interactions between I plus H, B or N. Bioequivalence between single and combined administrations was verified for all investigational compounds [AUC point estimates (90% confidence interval CI): imidaprilat IH 109% (97.8, 122.8); IB 99.6% (91.2, 109.4); IN 105.7% (92.1, 121.3); H 96.6% (92.5, 100.8); B 103% (100.2, 105.8); N 98% (89, 108)]. The haemodynamic effects were mostly additive and without relevant pharmacodynamic interactions. I significantly reduced the BP by 5-8 mmHg, B by 4-8 mmHg and N by 4-6 mmHg. In addition, H induced a significant reduction of the preload as seen from STI, and B significantly reduced HR (-5 bpm). N induced a significant decrease in TPR (about 15% of baseline values) and showed corresponding changes in STI. PRA increased significantly following I alone (1.5-2.0 ng/ml/h), as well as combined with N (2.5 ng/ ml/h) or H (3.1 ng/ml/h). This increase was clearly blunted by the co-administration of B (0.6 ng/ml/h). The combination of imidapril with a diuretic, beta-adrenoceptor antagonist or calcium-channel blocker seems a reasonable and safe treatment option when striving for additive pharmacodynamic effects not accompanied by relevant pharmacokinetic interactions.