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, trand olapril, was administered daily for 10 days to 13 patients With chroni c renal failure [CRF; creatinine clearance (CL(CR)) 7-55 ml/min/1.73 m (2)) and 8 healthy volunteers (CL(CR) > 80 ml/min/1.73 m(2))]. Plasma ACE inhibition parameters were the same, irrespective of the degree of renal insufficiency, although renal failure tended to prolong ACE inh ibition. 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 (C-max) and CL(CR) (r = -0.676 day 1 and r = -0.864 day 10) and area under the concentration-time curve (AUC) and CL(CR) (r = -0.635 day 1 and r = - 0.794 day 10). The renal clearance of trandolaprilat showed significan t linear correlation (r = >0.885, p < 0.0001) with CL(CR) after single (r = 0.879) and repeated administration (r = 0.957). Significantly re duced excretion of trandolaprilat was seen only when the CL(CR) was <3 0 ml/min/1.73 m(2). A steady state had been achieved by 7 days in all patients, and extrapolation suggested that this was achieved in most c ases after 4 days. The drug was well tolerated. The effect of CRF on t he pharmacokinetics and pharmacodynamics of trandolaprilat is of signi ficance only when CL(CR) is <30 ml/min/1.73 m(2). Hence, in these pati ents the standard dose should be reduced.