Pharmacokinetics and pharmacodynamics of argatroban as studied by HPLC and functional methods: Implications in the monitoring and dosage-optimizations in cardiovascular patients

Argatroban is a peptidomimetic reversible thrombin inhibitor that has been used as an anticoagulant in clinical trials related to heparin-induced thrombocytopenia (HIT). To monitor the absolute concentrations of argatroban and to relate the safety and efficacy of this drug with the circulating levels and corresponding prolongation of the activated clotting time (ACT), a specific method for the absolute measurement of this drug was developed. Initial studies for the validation of method included the quantitation of argatroban in normal volunteers administered with escalating doses of argatroban (15-40 mu g/kg/min) on four consecutive days for 4 h (ARG 102 Study). Pre- and postinfusion samples were analyzed by using the high performance liquid chromatography (HPLC) method. Argatroban levels ranged from 0.5-4.5 mu g/mL, postinfusion (0.84 +/-. 0.23 [day 1], 1.55 +/- 0.34 [day 2], 2.92 +/- 0.15 [day 3], 3.04 +/- 0.49 [day 4]). A proportionate increase in the activated partial thromboplastin time (APTT) and ACT was observed. Similarly, ecarin clotting time (ECT) also provided comparable results. Argatroban levels were also measured in a PTCA trial where this agent was used as an anticoagulant at 350 mu g/kg bolus followed by 25 mu g/kg/min to regulate the ACT between 400-450 sec (ARG 310 Study). In this angioplasty study, the levels of argatroban correlated well with the ACT (r(2) > 0.8). In another clinical study, argatroban was used in conjunction with streptokinase for the management of acute myocardial infarction (AMI), the levels of this agent were quantitated at baseline and 2-8 h postthrombolysis (AMI Study). In the AMI study, mean argatroban levels at 2-8 h were between 1.5-2.0 mu g/mL. Upon completion of the infusion, a time dependence in circulating argatroban levels was noted. Since heparinization, hemodilution, hypofibrinogenimia due to thrombolysis influence the ACT levels, absolute quantitation of argatroban in these patients provides a reliable means of monitoring and dosage optimization of this anticoagulant. Based on these observations and additional pharmacokinetics data, it is proposed that the currently used dosage of 350 mu g/kg bolus followed by 25 mu g/kg/min infusion is optimal to achieve anticoagulation for interventional cardiovascular procedures. This translates into 3-5 mu g/mL circulating concentration. For therapeutic anticoagulation to mimic responses observed at an APTT of 70-100 sec, a bolus of 50 mu g/kg followed by 10 mu g/kg/min resulting in a circulating levels of approximately 1.0 mu g/mL concentration is recommended.