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

Background. Hirudin selectively inhibits thrombin without cofactors and is eliminated via the kidneys. Recombinant hirudin (r-hi) has a terminal elimi nation half-life (t(1/2)) of about 50 to 100 minutes. Coupling of polyethyl ene glycol (PEG) to r-hi, giving PEG-hirudin (PEG-Hi), prolongs its t(1/2) while enhancing efficiency. We looked at the pharmacodynamic and pharmacoki netic behavior of PEG-Hi in patients with impaired renal function. Methods. Anticoagulant activity and the pharmacokinetic parameters of a sin gle intravenous bolus injection of 0.05 mg/kg body weight PEG-Hi were studi ed in 38 subjects. They were assigned to five groups: group IA, creatinine clearance (C-Cr) greater than or equal to 80 mL/min, 8 healthy volunteers; group IB, C-Cr greater than or equal to 80 mL/min, 8 patients with normal r enal function); group II, C-Cr 79 to 50 mL/min, 7 patients with mild chroni c renal failure (CRF); group III, C-Cr, 49 to 20 mL/min, 10 patients with m oderate CRF; and group IV, C-Cr less than or equal to 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 hour s. Results;. PEG-I-Hi was well tolerated in all groups. No serious adverse eve nts were noted. C-max, values were similar in all groups; area under the cu rve (AUC) increased in patients from 2.9 +/- 1.0 mug.h/mL (IB) to 21.3 +/- 5.0 mug 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 (FE0- 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 (LB) to 0.8 +/- 0.5 mL/min (IV), and FE0-t f rom 40.2 +/- 18.9% (IB) to 12.6 +/- 13.0% (IV). Total plasma clearance of P EG-Hi was well correlated with C-Cr. Anti-IIa activity of PEG-Hi showed a c loser linear relationship to ecarin clotting time than to activated partial thromboplastin time. Conclusion. Hence, PEG-Hi is considered safe in patients with CRF, but dosi ng and/or dose intervals should be adjusted according to the severity of re nal impairment. Ecarin clotting time is well suited for safe and reliable m onitoring of PEG-Hi.