G. Lefevre et al., EFFECT OF RENAL IMPAIRMENT ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF DESIRUDIN, Clinical pharmacology and therapeutics, 62(1), 1997, pp. 50-59
Objective: To investigate the pharmacokinetics and pharmacodynamics of
desirudin in subjects with various degrees of renal impairment in com
parison with subjects with normal renal function. Methods: Fight subje
cts with normal renal function (creatinine clearance >90 ml/min) recei
ved 0.5 mg/kg desirudin intravenously over 30 minutes. Four subjects w
ith mild renal failure (creatinine clearance between 61 and 90 ml/min)
received 0.5 mg/kg. Five subjects with moderate renal failure (creati
nine clearance between 31 and 60 ml/min) received 0.25 mg/kg. Six subj
ects with severe renal failure (creatinine clearance <31 ml/min) recei
ved 0.125 mg/kg. Results: Specific maximum concentration values (maxim
um concentrations corrected to a dose of 1 mg/kg) increased slightly w
ith decreasing creatinine clearance. Mean specific area under the plas
ma concentration-time curve increased by a factor of 1.15, 2.83, and 7
.0 for subjects with mild, moderate, and severe renal failure, respect
ively, compared with healthy subjects, Total urinary excretion of desi
rudin was about 55% to 60% of the dose in all four groups; elimination
was delayed for subjects with moderate and severe renal failure, Tota
l and renal clearance of desirudin were proportional to creatinine cle
arance, Total plasma clearance of desirudin was proportional to renal
clearance of the drug, Prolongation of activated partial thromboplasti
n time was increased among subjects with moderate and severe renal fai
lure despite a dose reduction, Area under the dynamic activated partia
l thromboplastin time curve for subjects with moderate renal failure r
emained the same as that for healthy subjects despite a dose reduction
by a factor of two, Area under the dynamic curve increased by a facto
r of about 1.5 for subjects with severe renal failure despite a dose r
eduction by a factor of four. Conclusion: A dose reduction by a factor
of six is recommended for persons with severe renal failure.