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normal renal function. Its half-life is approximately 25 min (Fox et al., 1993; Robson, 2000; Robson et al., 2002; The Medicines Company, 2005). Peak bivalirudin plasma concentrations after a 15 min iv infusion are related to dose and occur within 5 min of completing the infusion (Fig. 2).

Bivalirudin has a volume of distribution of 0.24 L/kg and a clearance rate of approximately 3.4mL/min/kg (Fox et al., 1993). It is cleared from plasma by both renal mechanisms and cleavage by plasma proteases. Bivalirudin undergoes glomerular filtration, secretion in the proximal convoluted tubule, and reabsorption in the distal convoluted tubule. The peptides are then further degraded within the intracellular lysosomes (Robson, 2000; Robson et al., 2002). In a study by Fox and colleagues (1993), only 20% of bivalirudin was recovered in the urine.

Clearance of bivalirudin is accomplished predominately by proteolytic cleavage within plasma and elsewhere and accounts for approximately 80% of the drug's metabolism (Fox et al., 1993; Scatena, 2000; Robson et al., 2002; Warkentin and Greinacher, 2003). Indeed, proteolysis of bivalirudin appears to result mainly from thrombin, thus providing a mechanism of degradation that is independent of specific organ function (Bates and Weitz, 2000; Koster et al., 2002a,b). This results in degradation to individual amino acids and small, inactive peptide fragments (Carswell and Plosker, 2002).

Patients with renal insufficiency may need dose adjustments for bivalirudin, according to their degree of impairment (Table 1). In a study of 45 patients with normal to severe renal disease, Robson (2000) found that patients with normal kidneys (glomerular filtration rate [GFR] > 90 mL/min) and mildly impaired renal disease (GFR = 60-89 mL/min) had similar renal clearance levels and required no dose adjustments. The clearance rate was reduced by 45% in individuals with moderate renal impairment (GFR = 30-59 mL/min) and by 68% in persons with severe renal impairment (GFR < 30 mL/min). In dialysis-dependent patients, the clearance rate was reduced by 77% (Robson, 2000; Robson et al., 2002). The half-life of bivalirudin in patients with severe renal impairment is prolonged (about 1h) and in dialysis patients the half-life is approximately 3.5 h (Nawarskas and Anderson, 2001).

Some investigators have suggested that dose reductions might be considered in patients with moderate or severe kidney dysfunction, including those on dialysis (Irvin et al., 1999; Robson, 2000; Robson et al., 2002). However, in the setting of

TABLE 1 Bivalirudin Pharmacokinetic Parameters in Patients with Renal Impairment

Renal function

(glomerular filtration rate, mL/min)

Bivalirudin clearance (mL/min/kg)

Half-life (min)

Normal renal function

(>90 mL/min) Mild renal impairment

(60-89 mL/min) Moderate renal impairment (30-59 mL/min) Severe renal impairment

(10-29 mL/min)a Dialysis-dependent (while off dialysis) patientsb

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