Pharmacokinetics

Lepirudin is administered parenterally. Studies of plasma pharmacokinetics in healthy subjects reveal a two-compartment model. The initial plasma half-life (ty2a) of lepirudin is 8-12 min, after which it is distributed in the extracellular space.

Only 20% of lepirudin is found in the plasma, while the remaining 80% is in the extravascular compartment (Glusa, 1998). Lepirudin is not transported into the cerebrospinal fluid or breast milk (Refludan Package Insert, 2002; Lindhoff-Last et al., 2000a).

The terminal plasma elimination half-life (ty2ß) ranges from 0.8 to 1.7 h (mean, ~1.3 h or 80 min) following intravenous (iv) injection of bolus doses of 0.010.5 mg/kg and 1.1-2.0 h following continuous iv infusions over 6 h. Maximum activated partial thromboplastin time (aPTT) ratios occur about 10 min after iv bolus, 3-6 h following start of 6-h continuous iv infusion, and 2-3 h following subcutaneous (sc) administration (in patients with normal renal function). During iv infusion, therapeutic levels are usually reached within 30-60 min. This correlates well with the peak plasma lepirudin concentrations achieved with these different modes of application. The approved dose for lepirudin in patients with HIT and acute thrombosis (with normal renal function) is an iv bolus of 0.40 mg/kg, followed by an iv infusion of 0.15 mg/kg/h (Table 1). However, there is consistent experience that this dose is too high in most HIT patients (Lubenow et al., 2004, 2005; Hacquard et al., 2005; Tardy et al., 2006). Especially in elderly patients the bolus should be omitted and an initial infusion rate of 0.05-0.10 mg/kg/h commenced so as to avoid overdosage in case of unrecognized renal insufficiency. The infusion rate should then be adjusted according to aPTT every 4 h until a steady state is reached (Lubenow et al., 2004) (Fig. 2). The main indication for application of the bolus is acute life- or limb-threatening thrombosis.

Renal clearance (160-200 mL/min for an adult with normal body surface area of 1.73 m2) and degradation account for approximately 90% of the systemic clearance of lepirudin. The tv2ß of r-hirudin lengthens with deterioration of renal function (Markwardt, 1989; Nowak et al., 1991, 1992, 1997; Vanholder et al., 1994, 1997); in nephrectomized patients, it can be up to 120 h (Wittkowsky and Kondo, 2000; Dager and White, 2001; Fischer, 2002; Shepherd, 2002).

A clinically important observation is that renal blood flow decreases during anesthesia, so that the elimination half-life is prolonged to 3-5 h. If lepirudin is used intraoperatively, the dose should be reduced by 30-50%, and close monitoring is mandatory.

With sc administration, bioavailability is nearly 100%. Dose-ranging studies have shown that its concentration in the blood reaches 0.3-0.5 mg/mL after an sc dose of lepirudin of 0.5 mg/kg and about 0.7 mg/mL after an sc dose of 0.75 mg/ kg, making twice-daily injections effective (Schiele et al., 1994; Huhle et al., 2000a; Nowak, 2001). When administered subcutaneously, this drug is usually injected into an abdominal skin fold and reaches its peak concentration after 2-3 h. Lepirudin has been administered subcutaneously for long-term prophylaxis in HIT after the acute disease has been controlled (Huhle et al., 2000a). In one patient the drug was safely administered sc twice daily for 8 mo for antithrombotic therapy in the setting of malignant disease. Lepirudin has been administered sc as an adjunct to streptokinase in patients with acute myocardial infarction (MI) (Neuhaus et al., 1999) and in the outpatient management of acute MI (Begelman and Deitcher, 2002).

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