Pharmacodynamics and pharmacokinetics of polyethylene glycol-hirudin in patients with chronic renal failure.

Abstract

Hirudin selectively inhibits thrombin without cofactors and is eliminated via the kidneys. Recombinant hirudin (r-hi) has a terminal elimination half-life (t1/2) of about 50 to 100 minutes. Coupling of polyethylene glycol (PEG) to r-hi, giving PEG-hirudin (PEG-Hi), prolongs its t1/2 while enhancing efficacy. We looked at the pharmacodynamic and pharmacokinetic behavior of PEG-Hi in patients with impaired renal function. Anticoagulant activity and the pharmacokinetic parameters of a single intravenous bolus injection of 0.05 mg/kg body weight PEG-Hi were studied in 38 subjects. They were assigned to five groups: group IA, creatinine clearance (CCr) >/= 80 mL/min, 8 healthy volunteers; group IB, CCr >/= 80 mL/min, 8 patients with normal renal function); group II, CCr 79 to 50 mL/min, 7 patients with mild chronic renal failure (CRF); group III, CCr 49 to 20 mL/min, 10 patients with moderate CRF; and group IV, CCr </= 19 mL/min, 5 patients with severe CRF. Plasma and urine samples were collected from patients for up to 120 hours after dosing and from healthy volunteers for up to 24 hours. PEG-Hi was well tolerated in all groups. No serious adverse events were noted. Cmax values were similar in all groups; area under the curve (AUC) increased in patients from 2.9 +/- 1.0 microg. h/mL (IB) to 21.3 +/- 5.0 microg h/mL (IV). According to the severity of renal function, t1/2 was prolonged from 2 hours (IB) to 38.4 hours (IV), while total body clearance (CTB), renal clearance (CRenal), and recovery of PEG-Hi in the urine (FEo-t) decreased as follows: CTB from 23.3 +/- 6.6 (IB) to 2.9 +/- 0.6 mL/min (IV), CRenal from 7.8 +/- 5.0 (IB) to 0.8 +/- 0.5 mL/min (IV), and FEo-t from 40.2 +/- 18. 9% (IB) to 12.6 +/- 13.0% (IV). Total plasma clearance of PEG-Hi was well correlated with CCr. Anti-IIa activity of PEG-Hi showed a closer linear relationship to ecarin clotting time than to activated partial thromboplastin time. Hence, PEG-Hi is considered safe in patients with CRF, but dosing and/or dose intervals should be adjusted according to the severity of renal impairment. Ecarin clotting time is well suited for safe and reliable monitoring of PEG-Hi.