Pharmacokinetics of temocapril and temocaprilat after 14 once daily oral doses of temocapril in hypertensive patients with varying degrees of renal impairment

• Published in: British journal of clinical pharmacology Vol. 44; no. 6; pp. 531 - 536
• Main Authors: Püchler, K., Eckl, K. M., Fritsche, L., Renneisen, K., Neumayer, H.‐H., Sierakowski, B., Lavrijssen, A. T. J., Thomsen, T., Roots, I.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-12-1997; Blackwell Science
• Subjects: ACE inhibitor; Adult; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors - administration & dosage; Angiotensin-Converting Enzyme Inhibitors - adverse effects; Angiotensin-Converting Enzyme Inhibitors - pharmacokinetics; Antihypertensive agents; Area Under Curve; Biological and medical sciences; Cardiovascular system; Creatinine - blood; Female; Humans; Kidney Diseases - metabolism; Male; Medical sciences; Middle Aged; Original; pharmacokinetics; Pharmacology. Drug treatments; renal failure; temocapril; temocaprilat; Thiazepines - administration & dosage; Thiazepines - adverse effects; Thiazepines - pharmacokinetics; Kidney disease; Human; Hypertension; Dosage adjustment; Urinary system disease; Metabolite; Elimination; Oral administration; Cardiovascular disease; Metabolism; Multiple dose; Absorption; Association; Interindividual comparison; Renal failure; Antihypertensive agent; Complication; ACE inhibitor; Temocapril
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1046/j.1365-2125.1997.t01-1-00622.x

Aims The aim of this study was to determine the potential influence of renal impairment on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat.
Methods Non‐compartmental pharmacokinetics were assessed in four groups of hypertensive patients (n=8 per group, four investigational centres) with normal (creatinine clearance determined via 24 h urine sampling, CLCR, ≥60 ml min−1 ) and impaired renal function (CLCR 40–59, 20–39, <20 ml min−1 ) after 14 once daily oral doses of 10 mg temocapril hydrochloride.
Results For temocapril, there were no statistically significant differences in median tmax or mean Cmax, AUCSS, t½,Z, CL/F between the four groups. Renal clearance, CLR, for temocapril showed a linear decreasing trend with decreasing CLCR [
mean (s.d.): 32.2 (10.7) to 3.7 (3.0) ml min−1]. Steady‐state for temocaprilat was reached on day 5. For temocaprilat, no statistically significant differences in mean Cmax or median tmax were detected. With decreasing mean CLCR, mean AUCSS for temocaprilat increased statistically significantly although only 2.4‐fold [mean (s.d.): 2115 (565) to 4989 (2338) ng ml−1 h] and t½,Z was prolonged [mean (s.d.): 15.2 (1.2) to 20.0 (7.5) h]. CLR for temocaprilat showed a linear decreasing trend with decreasing CLCR [mean (s.d.): 20.2 (4.3) to 3.0 (1.8) ml min−1].
Conclusions These results indicate that impaired renal function has only a limited effect on the pharmacokinetics of temocapril and its active metabolite, temocaprilat. This may be attributed to the dual, i.e. renal and biliary, elimination pathway of the drug.