Pharmacology

The pharmacodynamic impact of factor Xa inhibition is reduced thrombin generation. Studies performed in vitro with platelet-rich plasma have identified an inhibitory effect on both the initiation and propagation phases of thrombin generation, with reduction in the total amount of thrombin generated (Walenga et al., 1988; Gerotziafas et al., 2004). Animal studies have demonstrated pronounced inhibition of thrombus extension (Amar et al., 1990).

The pharmacokinetics of fondaparinux were determined in young, healthy volunteers and in the elderly (Donat et al., 2002). Following subcutaneous (sc) injection, fondaparinux is absorbed completely, with peak plasma concentrations achieved within 1-3 h. Maximal concentrations and area-under-the-curve correlate linearly with dose, with the half-life being relatively constant in young volunteers (~17h). In the elderly, the half-life is mildly prolonged (~21h). The comparatively long elimination half-life permits a once-daily sc dosing schedule, with steady-state achieved following the fourth or fifth daily dose. Fondaparinux is excreted almost completely in the urine without metabolism.

The pharmacology of fondaparinux has not been well defined in special populations, such as pregnant women, children, or persons with severe renal impairment. Data from the orthopedic thromboprophylaxis trials provides insights into the impact of renal impairment on drug clearance (Turpie, 2002). With mild renal impairment (creatinine clearance, 50-80 mL/min), fondaparinux clearance is reduced by 25%; with moderate renal impairment (creatinine clearance, 3050 mL/min), clearance is 40% reduced (Arixtra Package Insert, 2006). Thus, use of fondaparinux is not advised with severe renal impairment (creatinine clearance, <30mL/min). The safe, effective use of fondaparinux in pregnant patients has been reported in several case reports (Harenberg, 2007; Mazzolai et al., 2006; Wijesiriwardana et al., 2006). Despite in vitro evidence to the contrary, transpla-cental passage of fondaparinux has been suggested by the detection of a low antifactor Xa activity in umbilical cord blood, so caution in this context is warranted (Dempfle, 2004; Lagrange et al., 2002).

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