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(cr)), 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 microg/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.
Arpino
Paul A
PA
Department of Pharmacy, Massachusetts General Hospital, Boston, MA 02114, USA. parpino@partners.org
Hallisey
Robert K
RK
D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives; D003404:Creatinine / Q000097:blood; D003625:Data Collection; D004334:Drug Administration Schedule; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000502:physiology*; D007677:Kidney Function Tests; D008111:Liver Function Tests; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D018579:Patient Selection; D010875:Pipecolic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011446:Prospective Studies; D013449:Sulfonamides; D016896:Treatment Outcome
D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; D003404:Creatinine; C031942:argatroban