Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2 mg to patients with chronic renal failure and healthy control subjects.
A new, long-acting angiotensin-converting enzyme (ACE) inhibitor, trandolapril, was administered daily for 10 days to 13 patients with chronic renal failure [CRF; creatinine clearance (CLCR) 7-55 ml/min/1.73 m2) and 8 healthy volunteers (CLCR > 80 ml/min/1.73 m2)]. Plasma ACE inhibition parameters were the same, irrespective of the degree of renal insufficiency, although renal failure tended to prolong ACE inhibition. The pharmacokinetics of trandolapril were not affected by CRF; hence, no accumulation of trandolapril was detected. After single or repeated administration the active metabolite, trandolaprilat, showed an inverse correlation between maximal plasma concentrations (Cmax) and CLCR (r = -0.676 day 1 and r = -0.864 day 10) and area under the concentration-time curve (AUC) and CLCR (r = -0.635 day 1 and r = -0.794 day 10). The renal clearance of trandolaprilat showed significant linear correlation (r = > 0.885, p < 0.0001) with CLCR after single (r = 0.879) and repeated administration (r = 0.957). Significantly reduced excretion of trandolaprilat was seen only when the CLCR was < 30 ml/min/1.73 m2. A steady state had been achieved by 7 days in all patients, and extrapolation suggested that this was achieved in most cases after 4 days. The drug was well tolerated. The effect of CRF on the pharmacokinetics and pharmacodynamics of trandolaprilat is of significance only when CLCR is < 30 ml/min/1.73 m2. Hence, in these patients the standard dose should be reduced.
Danielson
B
B
Department of Medicine, University Hospital, Uppsala, Sweden.
Querin
S
S
LaRochelle
P
P
Sultan
E
E
Mouren
M
M
Bryce
T
T
Stepniewski
J P
JP
Lenfant
B
B
D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; C052035:trandolapril; C061095:trandolaprilat