Objective: Intermittent activation of the renin-angiotensin system during dialysis may be related to the high risk of cardiovascular disease in dialysis patients. The aim of the present study was to investigate the pharmacokinetics and short-term tolerability of the angiotensin II type 1 receptor antagonist candesartan cilexetil in patients receiving chronic haemodialysis.
Design: The study was a double-blind, randomised, placebo-controlled, dose-escalation study. Candesartan cilexetil was administered once daily, starting at 4mg with up-titration biweekly to 8mg and 16mg, respectively. Trough plasma concentrations of candesartan were determined before dialysis. After 2 weeks on the highest dose, plasma concentrations were obtained at frequent intervals after dose administration.
Patients: Twenty patients receiving chronic haemodialysis and with adequately controlled blood pressure were included in the study. Fourteen patients were randomised to candesartan cilexetil and six to placebo.
Results: Nine of the patients randomised to candesartan cilexitil reached the maximum dose of 16mg and completed the study according to protocol. Their blood pressure remained stable. Four patients discontinued active treatment due to hypotension at the lowest dose. Trough plasma concentrations of candesartan determined at the end of each study period increased linearly with dose. Following administration of candesartan cilexetil 16mg the maximum plasma concentration of candesartan was 244 +/- 54 mug/L and the area under the concentration-time curve over 24 hours, i.e. one dosing interval (AUC(tau)), was 2767 +/- 1162 mug/L . h.
Conclusion: Steady-state plasma concentrations of candesartan were approximately twice as high in haemodialysis patients as in subjects with normal renal function. Provided blood pressure is carefully monitored, candesartan cilexetil can be titrated from 4mg up to 16mg once daily in haemodialysis patients.