Pharmacokinetics of valsartan in patients with liver disease.

OBJECTIVES: Valsartan (CGP 48933), an orally active angiotensin II antagonist, is eliminated mainly by hepatic clearance. To characterize the compound(s) excreted in the bile, biliary excretion of valsartan was investigated by collection of bile after an intravenous dose of valsartan. In addition, to determine the exposure to valsartan when liver function is impaired, a pharmacokinetic study (open, single dose) was performed in patients with mild and moderate impairment of liver function. PATIENTS: Biliary excretion of valsartan (after intravenous administration of 20 mg valsartan) was assessed in a patient who underwent a hepaticojejunostomy with subsequent bile drainage. Exposure to valsartan in patients with mild (n = 6) or moderate (n = 6) impaired liver function (Child's-Pugh classification) and matching (sex, age, and weight) healthy volunteers (n = 12) was studied after oral administration of a single dose of 160 mg valsartan. RESULTS: After intravenous administration, valsartan was eliminated mainly as unchanged drug in the bile. Mean exposure (measured as area under the plasma valsartan concentration-time curve) to valsartan was increased about twofold in both the mild and the moderate groups compared with matched (age, sex, and weight) healthy volunteers. CONCLUSION: These data are consistent with the pharmacokinetics of valsartan in that biliary excretion is the main route of elimination.

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. CONCLUSION: A dose reduction by a factor of six is recommended for persons with severe renal failure.