Pharmacokinetics and protein binding of eprosartan in hemodialysis-dependent patients with end-stage renal disease.
OBJECTIVE
To compare eprosartan pharmacokinetics in hemodialysis patients and in volunteers with normal renal function, and to determine the effect of hemodialysis on these values.


METHODS
Open-label, parallel-group, single-dose study.


METHODS
Outpatient hemodialysis treatment center and an industry-affiliated clinical pharmacology unit.


METHODS
Ten healthy volunteers and nine hemodialysis patients.


METHODS
A single oral dose of eprosartan 400 mg was administered to volunteers on 1 day and to patients on 2 days (a nondialysis and a dialysis day). Patients underwent high-flux hemodialysis.


RESULTS
Concentrations of eprosartan in plasma and dialysate were assayed by high-performance liquid chromatography; plasma protein binding was determined by ultrafiltration. Eprosartan pharmacokinetics showed greater variability in patients than in volunteers. However, six of nine patients had exposures that were within the range observed for volunteers. Mean total AUC(0-t) was increased approximately 60% (95% CI-22, 225) in patients. Total Cmax was similar between groups (PE = 1.01, 95% CI -40, 71). Mean percent fraction unbound (%f(u)) in patients (3.02%) was significantly greater than that in volunteers (1.74%). Unbound AUC(0-t) and unbound Cmax were, on average, approximately 172% (95% CI 28, 479) and 73% (95% CI -1, 199) greater, respectively, in patients. After hemodialysis, the mean %f(u) decreased from 3.19-2.01%. Mean recovery of eprosartan in dialysate was 6.8 mg (range 0-23.1 mg) and hemodialytic clearance was approximately 11 ml/minute, which does not represent a significant portion of total clearance.


CONCLUSIONS
Eprosartan was safe and well tolerated in both groups. Based on its known safety profile and because of its exaggerated pharmacokinetic variability in patients undergoing hemodialysis, treatment should be individualized based on tolerability and response. Supplemental doses of eprosartan after hemodialysis are unnecessary.
Kovacs
S J
SJ
SmithKline Beecham Clinical Pharmacology Unit, Presbyterian Medical Center-University of Pennsylvania Health System, Philadelphia 19104, USA.
Tenero
D M
DM
Martin
D E
DE
Ilson
B E
BE
Jorkasky
D K
DK
D000179:Acrylates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000378:metabolism*; D013876:Thiophenes
D000179:Acrylates; D000959:Antihypertensive Agents; D007093:Imidazoles; D013876:Thiophenes; C068373:eprosartan