Fondaparinux

Fondaparinux is a synthetic and selective inhibitor of activated Factor X (Xa). The antithrombotic activity of fondaparinux is the result of antithrombin III (ATIII) mediated selective inhibition of Factor Xa. By binding selectively to ATIII, fondaparinux potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralisation of Factor Xa interrupts the blood coagulation cascade and inhibits both thrombin formation and thrombus development. Fondaparinux does not inactivate thrombin (activated Factor II) and has no effects on platelets.

At the 2.5 mg dose, fondaparinux does not affect routine coagulation tests such as activated partial thromboplastin time (aPTT), activated clotting time (ACT) or prothrombin time (PT)/International Normalised Ratio (INR) tests in plasma nor bleeding time or fibrinolytic activity. However, rare spontaneous reports of aPTT prolongation have been received.

Fondaparinux does not usually cross-react with sera from patients with heparin-induced thrombocytopaenia (HIT). However, rare spontaneous reports of HIT in patients treated with fondaparinux have been received.

Absorption

After subcutaneous dosing, fondaparinux is completely and rapidly absorbed (absolute bioavailability 100%). Following a single subcutaneous injection of fondaparinux 2.5 mg to young healthy subjects, peak plasma concentration (mean C_max = 0.34 mg/l) is obtained 2 hours post-dosing. Plasma concentrations of half the mean C_max values are reached 25 minutes post-dosing.

In elderly healthy subjects, pharmacokinetics of fondaparinux are linear in the range of 2 to 8 mg by subcutaneous route. Following once daily dosing, steady state of plasma levels is obtained after 3 to 4 days with a 1.3-fold increase in C_max and AUC.

Mean (CV%) steady state pharmacokinetic parameters estimates of fondaparinux in patients undergoing hip replacement surgery receiving fondaparinux 2.5 mg once daily are: C_max (mg/l) - 0.39 (31%), T_max (h) - 2.8 (18%) and C_min (mg/l) - 0.14 (56%). In hip fracture patients, associated with their increased age, fondaparinux steady state plasma concentrations are: C_max (mg/l) - 0.50 (32%), C_min (mg/l) - 0.19 (58%).

In DVT and PE treatment, patients receiving fondaparinux 5 mg (body weight <50 kg), 7.5 mg (body weight 50-100 kg inclusive) and 10 mg (body weight >100 kg) once daily, the body weight-adjusted doses provide similar exposure across all body weight categories. The mean (CV%) steady state pharmacokinetic parameters estimates of fondaparinux in patients with VTE receiving the fondaparinux proposed dose regimen once daily are: C_max (mg/l) - 1.41 (23 ), T_max (h) – 2.4 (8) and C_min (mg/l) -0.52 (45 %). The associated 5^th and 95^th percentiles are, respectively, 0.97 and 1.92 for C_max (mg/l), and 0.24 and 0.95 for C_min (mg/l).

Distribution

The distribution volume of fondaparinux is limited (7-11 litres). In vitro, fondaparinux is highly and specifically bound to antithrombin protein with a dose-dependant plasma concentration binding (98.6% to 97.0% in the concentration range from 0.5 to 2 mg/l). Fondaparinux does not bind significantly to other plasma proteins, including platelet factor 4 (PF4).

Since fondaparinux does not bind significantly to plasma proteins other than ATIII, no interaction with other medicinal products by protein binding displacement are expected.

Biotransformation

Although not fully evaluated, there is no evidence of fondaparinux metabolism and in particular no evidence for the formation of active metabolites.

Fondaparinux does not inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4) in vitro. Thus, fondaparinux is not expected to interact with other medicinal products in vivo by inhibition of CYP-mediated metabolism.

Elimination

The elimination half-life (ty2) is about 17 hours in healthy young subjects and about 21 hours in healthy elderly subjects. Fondaparinux is excreted to 64 – 77 % by the kidney as unchanged compound.

Special populations

Paediatric patients

Fondaparinux has not been investigated in this population for the prevention of VTE or for the treatment of superficial vein thrombosis.

Elderly patients

Renal function may decrease with age and thus, the elimination capacity for fondaparinux may be reduced in elderly. In patients >75 years undergoing orthopaedic surgery, the estimated plasma clearance was 1.2 to 1.4 times lower than in patients <65 years.

Renal impairment

Compared with patients with normal renal function (creatinine clearance >80 ml/min), plasma clearance is 1.2 to 1.4 times lower in patients with mild renal impairment (creatinine clearance 50 to 80 ml/min) and on average 2 times lower in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min). In severe renal impairment (creatinine clearance <30 ml/min), plasma clearance is approximately 5 times lower than in normal renal function. Associated terminal half-life values were 29 h in moderate and 72 h in patients with severe renal impairment.

Gender

No gender differences were observed after adjustment for body weight.

Race

Pharmacokinetic differences due to race have not been studied prospectively. However, studies performed in Asian (Japanese) healthy subjects did not reveal a different pharmacokinetic profile compared to Caucasian healthy subjects. Similarly, no plasma clearance differences were observed between black and Caucasian patients undergoing orthopaedic surgery.

Body weight

Plasma clearance of fondaparinux increases with body weight (9% increase per 10 kg).

Hepatic impairment

Following a single, subcutaneous dose of fondaparinux in subjects with moderate hepatic impairment (Child-Pugh Category B), total (i.e. bound and unbound) C_max and AUC were decreased by 22% and 39%, respectively, as compared to subjects with normal liver function. The lower plasma concentrations of fondaparinux were attributed to reduced binding to ATIII secondary to the lower ATIII plasma concentrations in subjects with hepatic impairment thereby resulting in increased renal clearance of fondaparinux. Consequently, unbound concentrations of fondaparinux are expected to be unchanged in patients with mild to moderate hepatic impairment, and therefore, no dose adjustment is necessary based on pharmacokinetics.

The pharmacokinetics of fondaparinux has not been studied in patients with severe hepatic impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity. Animal studies are insufficient with respect to effects on toxicity to reproduction because of limited exposure.