Influence of renal dysfunction on the pharmacokinetics of the selective Na+/H+ exchange inhibitor EMD 87 580 in patients with chronic heart failure.
BACKGROUND
Chronic heart failure (CHF) is a potential indication for the administration of EMD 87 580, a selective Na+/H+ exchange inhibitor. CHF is often accompanied by renal dysfunction, which is known to affect the pharmacokinetics of compounds predominately cleared by the kidneys. We examined the influence of renal dysfunction on the pharmacokinetics of EMD 87 580 in patients with CHF.


METHODS
21 patients with CHF and normal renal function (Group 1) and 9 patients with CHF and renal dysfunction (Group 2) received EMD 87 580 orally over 8 days. The mean creatinine clearance (CrCl) in Group 1 was 99.7 ml/min. 12 patients in this group were randomized to receive two doses of EMD 87 580 (7 patients 2 x 50 mg and 5 patients 2 x 100 mg). The 9 patients in Group 2 with renal dysfunction (mean CrCl = 49.5 ml/min) received 50 mg EMD 87 580 once daily. Plasma and urine samples were collected for pharmacokinetic assessment.


RESULTS
In CHF patients with renal dysfunction EMD 87 580 clearance was reduced to approximately 50% compared to Group 1, i.e. 6.80 ml/min (4.89-11.60) vs. 12.73 ml/min (8.93-22.21), p < 0.05, for the 50 mg dose and 14.08 ml/min (9.96-18.10), p < 0.05, for the 100 mg dose. Consequently, plasma concentrations were increased in patients with renal dysfunction; AUC0-infinity 7,354 ng/ml x h (4,311-10,232) vs. 3,928 ng/ml x h (2,251-5,596, 50 mg dose, p < 0.05). A significant correlation was observed between EMD 87 580 plasma clearance and CrCl (r2 = 0.8062).


CONCLUSIONS
In CHF patients with renal dysfunction EMD 87 580, clearance is reduced and plasma concentrations increased. Therefore, dose adjustments for EMD 87 580 are indicated in patients with CHF and renal dysfunction.
Smilde
T D J
TD
Department of Cardiology, Thoraxcenter, University Medical Center Groningen, The Netherlands. t.d.j.smilde@thorax.azg.nl
Linssen
G C M
GC
Gallemann
D
D
Kuhn
T
T
Machnig
T
T
Mol
P G M
PG
Hillege
H L
HL
Van Wijk
L M
LM
Van Dijk
R B
RB
Van Veldhuisen
D J
DJ
D000368:Aged; D003404:Creatinine / Q000378:metabolism; D005260:Female; D005919:Glomerular Filtration Rate; D006146:Guanidines / Q000097:blood / Q000493:pharmacokinetics*; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D013450:Sulfones / Q000097:blood / Q000493:pharmacokinetics*
D006146:Guanidines; C481648:N-(2-methyl-4,5-bis(methylsulfonyl)benzoyl)guanidine; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; D003404:Creatinine