Effect of renal function on the pharmacodynamics of argatroban

BACKGROUND: Argatroban is a direct thrombin inhibitor used to treat heparin-induced thrombocytopenia (HIT). Argatroban is primarily cleared by hepatic mechanisms, with only small amounts of unchanged drug cleared by the kidneys. OBJECTIVE: To assess the effects of renal function on argatroban dose and activated partial thromboplastin time (aPTT). METHODS: Patients treated with argatroban were identified and prospectively screened. Patients with liver dysfunction were excluded from the analysis. Charts and laboratory data were reviewed daily until a therapeutic aPTT was reached or argatroban was discontinued. Data points collected included age, weight, gender, admitting diagnosis, past medical history, indication for anticoagulation, indication for argatroban, initial dose, goal aPTT, titration instructions, liver function tests, serum creatinine (S,,), blood urea nitrogen, and estimated creatinine clearance (Cl-cr). RESULTS: A total of 66 patients were evaluated and 44 met criteria for inclusion. Baseline S-cr was elevated at 1.5 mg/dL (0.9, 2.3; median 25th, 75th percentile), with an estimated Cl-cr 40 mL/min/1.73 m(2) (26, 74). The median dose of argatroban to reach the predefined therapeutic range was 1 mug/kg/min (0.68, 2), with a corresponding aPTT of 60 seconds (54, 66). After univariate analysis, Cl-cr significantly predicted the therapeutic dose (coefficient b +/- SE 0.019 +/- 0.004; r(2) 0.35; p < 0.001). Covariates that predicted dose were the presence of HIT (coefficient b +/- SE -0.61 +/- 0.3; p = 0.045), history of myocardial infarction (coefficient b +/- SE -0.74 +/- 0.3; p = 0.02), and an indication for anticoagulation of deep-vein thrombosis/pulmonary embolism (coefficient b +/- SE 0.69 +/- 0.3; p = 0.03). CONCLUSIONS: Estimated Cl-cr significantly predicted the dose of argatroban needed to reach a therapeutic aPTT.