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

Abstract

Background. Hirudin selectively inhibits thrombin without cofactors and is eliminated via the kidneys. Recombinant hirudin (r-hi) has a terminal elimination half-life (t(1/2)) of about 50 to 100 minutes. Coupling of polyethylene glycol (PEG) to r-hi, giving PEG-hirudin (PEG-Hi), prolongs its t(1/2) while enhancing efficacy. We looked at the pharmacodynamic and pharmacokinetic behavior of PEG-Hi in patients with impaired renal function. Methods. 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 (C(Cr)) ≥ 80 mL/min, 8 healthy volunteers; group IB, C(Cr) ≥ 80 mL/min, 8 patients with normal renal function); group II, C(Cr) 79 to 50 mL/min, 7 patients with mild chronic renal failure (CRF); group III, C(Cr) 49 to 20 mL/min, 10 patients with moderate CRF; and group IV, C(Cr) ≤ 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. Results. PEG-Hi was well tolerated in all groups. No serious adverse events were noted. C(max) values were similar in all groups; area under the curve (AUC) increased in patients from 2.9 ± 1.0 μg · h/mL (IB) to 21.3 ± 5.0 μg h/mL (IV). According to the severity of renal function, t(1/2) was prolonged from 2 hours (IB) to 38.4 hours (IV), while total body clearance (C(TB)), renal clearance (C(Renal)), and recovery of PEG-Hi in the urine (FE(o-t) decreased as follows: C(TB) from 23.3 ± 6.6 (IB) to 2.9 ± 0.6 mL/min (IV), C(Renal) from 7.8 ± 5.0 (IB) to 0.8 ± 0.5 mL/min (IV), and FE(o-t) from 40.2 ± 18.9% (IB) to 12.6 ± 13.0% (IV). Total plasma clearance of PEG-Hi was well correlated with C(Cr). Anti-IIa activity of PEG-Hi showed a closer linear relationship to ecarin clotting time than to activated partial thromboplastin time. Conclusion. 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.