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 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.