Pharmacokinetic Pharmacodynamic Relationship

The pharmacokinetic and pharmacodynamic profiles of intravenous (iv) argatro-ban are consistent with an anticoagulant agent that is predictable, has a fast onset of action, and is rapidly eliminated (Swan and Hursting, 2000; Swan et al., 2000).

The anticoagulant effects of argatroban are routinely monitored using the activated partial thromboplastin time (aPTT). Higher levels of anticoagulation, such as that required during interventional procedures, are monitored using the activated clotting time (ACT). Argatroban also increases in a dose-dependent fashion the prothrombin time (PT)/International Normalized Ratio (INR), thrombin time, and ecarin clotting time (Nagasawa et al., 1981; Clark et al., 1991; Walenga et al., 1999; Swan et al., 2000; Sheth et al., 2001). High-performance liquid chromatography (Rawson et al., 1993; Walenga et al., 1999) and liquid chromato-graphy/tandem mass spectrometry (Tran et al., 1999) methods for measuring plasma argatroban are described but not practical (or needed) for routine monitoring.

Immediately upon initiation of argatroban infusion, anticoagulant effects are produced as plasma argatroban concentrations begin to rise. Steady-state levels of both drug and anticoagulant effect typically are attained within 1-3 h (faster when a loading bolus is administered) and maintained with low intra- and intersubject variability until the infusion is discontinued or the dosage adjusted. Plasma drug concentrations increase proportionally with doses up to 40 mg/kg/min and are well correlated with steady-state anticoagulant effects. The relationship at steady state between argatroban dose up to 10 mg/kg/min, plasma argatroban concentration, and aPTT is shown in Figure 3. When infusion is stopped, plasma argatroban concentrations decline rapidly (half-life of 39-51 min), and anticoagulant effects return to pretreatment values with similar effect half-lives (Swan et al., 2000).

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