Pharmacokinetics of candesartan cilexetil in patients with renal or hepatic impairment.

Five clinical studies were conducted to investigate the pharmacokinetic profile and safety of candesartan cilexetil in patients with either normal or impaired renal or hepatic function. Participants in these open-label, single- or parallel-group prospective studies were administered candesartan cilexetil 8 or 12 mg as a single oral dose and then, in all but one study, as a repeated once-daily oral dose regimen. A total of 94 patients of either gender aged between 18 and 75 years with normal or mild to moderate hepatic dysfunction (Study 1) and normal or mild to moderate/severe renal dysfunction (Studies 2-5) were included. Subjects recruited to all studies evaluating the effect of renal impairment also had some degree of hypertension. Patients with mild to moderate hepatic impairment showed no significant differences in the key plasma pharmacokinetic parameters or plasma protein binding profile of candesartan compared with healthy volunteers. In patients with mild to moderate or severe renal impairment there were significant increases in the maximum plasma concentration, area under the plasma drug concentration-time curve and elimination half-life of candesartan and its inactive metabolite (CV-15959) when compared to volunteers with normal renal function following repeated administration of candesartan cilexetil 8 or 12 mg. However, there was no evidence of accumulation following treatment with the 8 mg dose apart from those with severe disease requiring dialysis. Nevertheless, dialysis itself did not appear to affect the pharmacokinetic profile of candesartan or that of CV-15959. Candesartan cilexetil was found to have a good safety profile and to be well tolerated by patients with hepatic or renal impairment. There were no clinically relevant changes detected in vital signs, laboratory safety parameters or in ECG readings. The most common adverse events were headache and dizziness. This series of studies show that candesartan cilexetil 8 mg once daily is suitable for administration to patients with mild to moderate renal or hepatic impairment with no need for additional dose adjustment. A lower starting dose may be appropriate in patients with severe renal impairment including those requiring dialysis.