Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin.
OBJECTIVE
To investigate the pharmacokinetics and pharmacodynamics of desirudin in subjects with various degrees of renal impairment in comparison with subjects with normal renal function.


METHODS
Eight subjects with normal renal function (creatinine clearance > 90 ml/min) received 0.5 mg/kg desirudin intravenously over 30 minutes. Four subjects with mild renal failure (creatinine clearance between 61 and 90 ml/min) received 0.5 mg/kg. Five subjects with moderate renal failure (creatinine clearance between 31 and 60 ml/min) received 0.25 mg/kg. Six subjects with severe renal failure (creatinine clearance < 31 ml/min) received 0.125 mg/kg.


RESULTS
Specific maximum concentration values (maximum concentrations corrected to a dose of 1 mg/kg) increased slightly with decreasing creatinine clearance. Mean specific area under the plasma concentration-time curve increased by a factor of 1.15, 2.83, and 7.0 for subjects with mild, moderate, and severe renal failure, respectively, compared with healthy subjects. Total urinary excretion of desirudin was about 55% to 60% of the dose in all four groups; elimination was delayed for subjects with moderate and severe renal failure. Total and renal clearance of desirudin were proportional to creatinine clearance. Total plasma clearance of desirudin was proportional to renal clearance of the drug. Prolongation of activated partial thromboplastin time was increased among subjects with moderate and severe renal failure despite a dose reduction. Area under the dynamic activated partial thromboplastin time curve for subjects with moderate renal failure remained the same as that for healthy subjects despite a dose reduction by a factor of two. Area under the dynamic curve increased by a factor of about 1.5 for subjects with severe renal failure despite a dose reduction by a factor of four.


CONCLUSIONS
A dose reduction by a factor of six is recommended for persons with severe renal failure.
Lefèvre
G
G
Laboratoires Ciba-Geigy, Ruell-Malmaison, France.
Duval
M
M
Gauron
S
S
Brookman
L J
LJ
Rolan
P E
PE
Morris
T M
TM
Piraino
A J
AJ
Morgan
J M
JM
Palmisano
M
M
Close
P
P
D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003404:Creatinine / Q000097:blood; D005260:Female; D006629:Hirudins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D051437:Renal Insufficiency / Q000097:blood / Q000378:metabolism* / Q000652:urine; D012720:Severity of Illness Index
D000925:Anticoagulants; D006629:Hirudins; D011994:Recombinant Proteins; D003404:Creatinine; C060225:desirudin