Pharmacokinetics and haemodynamics of candesartan cilexetil in hypertensive patients on regular haemodialysis

Abstract

Aims: The pharmacokinetic profile of candesartan cilexetil might be altered in patients with end-stage renal disease (ESRD). No data are available about the pharmacokinetics and haemodynamics of the angiotensin II receptor antagonist candesartan cilexetil in ESRD patients on regular haemodialysis (HD).

Methods: We performed a repeated dose study (8 mg candesartan cilexetil once daily) in eight male HD patients over a treatment period of 5 days with an additional observation period of 3 days.

Results: Pharmacokinetic analysis with nonlinear mixed effects modeling (NONMEM) over the whole treatment period revealed a dependency of the volume of distribution on body weight and of the metabolic clearance on age and body weight in the studied population. No significant drug elimination by HD was observed. The estimated metabolic and intercompartmental clearances were 83 ml min-1 (CV 39%) and 9.9 ml min-1, respectively. The unexplained random variability of the final two compartment model was 30%. In one patient with adult polycystic kidney disease oral clearance decreased during the observation period, attributable to a significant increase in bioavailability. Maximum observed changes in blood pressure were -50/-27+/-14/8 mmHg on day 5 with haemodialysis therapy as compared with changes in blood pressure of -14/-12+/-14/8 mmHg on day 1 without haemodialysis treatment. The observed maximum decrease in systolic blood pressure correlated with the amount of ultrafiltration during the HD session on day 5 (r=0.70, P<0.05). In two patients, one of whom was binephrectomized, severe hypotensive episodes were observed during this HD session.

Conclusions: HD does not influence the elimination kinetics of candesartan. The observed inter- and intraindividual variability of oral clearance and the pronounced influence of HD-induced volume contraction on the haemodynamic effects of candesartan makes it mandatory to carefully monitor HD patients treated with candesartan cilexetil.

Figure 1

Observed changes in blood pressure and heart rate over the whole observation period of 8 days. A haemodialysis procedure was performed on days 2 or 3 and on days 5 and 7. The dotted lines represent the mean values of the measured blood pressures and heart rates, respectively. The error bars denote the corresponding standard deviations.

Figure 2

Relationship between predicted and measured candesartan serum levels. Open circles represent the data of the patient with much higher candesartan levels on day 5 to 8 as compared with the other seven patients (black circles). The line represents the identity line. a) A basic two-compartment model is assumed. b) Expansion of the basic two-compartment model (panel a) by relating the peripheral volume of distribution to body weight and by relating the metabolic clearance to age and body weight (see Appendix). c) Improvement of the expanded two-compartment model (panel b) by allowing for an individual oral clearance for the patient with increased candesartan levels from days 5 to 8.