Validation of Pharmacokinetic {PK} Simulation for Fondaparinux (FPX) Dosing by FPX-Specific Anti-Factor Xa Assay in Elderly Cancer Patients with Severe Renal Dysfunction

Background: Fondaparinux (FPX) is a synthetic pentasaccharide inhibitor of factor Xa indicated for prophylaxis and treatment of venous thromboembolism (VTE). It has an 18 hr half-life (T _1/2), thus is suitable for once-daily dosing, but is cleared by the kidney and not recommended for patients with SRD (creatinine clearance (CrCl) <30 mL/min) in whom drug accumulation could increase bleeding risk. No published clinical trials have evaluated the use of FPX in this population. However, in a pharmacokinetic simulation, serum FPX concentrations in such patients receiving FPX for VTE prophylaxis every other day were predicted to be similar to those in patients with mild renal impairment on daily dosing. Validation of this dosing regimen with an automated assay that determines anti-factor Xa activity levels using FPX calibrators could make this versatile drug accessible to many hypercoagulable patients with severe renal dysfunction

Methods: A retrospective analysis of institutional pharmacokinetic protocol outcomes was conducted in a small population of elderly cancer patients with chronic or acute-on- chronic SRD (CrCl < 30ml/min for >72 hrs) who received subcutaneous FPX 2.5 mg every 48 hrs for VTE prophylaxis. Peak and trough levels were determined at 3 hours post-dose and 1hr pre-dose respectively, for at least 3 doses. FPX levels were assayed with FPX-specific calibrators.

Descriptive data appear in Table 1.

Results: Eight patients were included in this study with mean age of 69.5 ± 11.5 years and creatinine clearance of 19 ± 7.9 mL/min. The mean peak FPX concentration was 0.39 ± 0.13 mcg/mL, in the lower target range for prophylaxis efficacy (0.39–0.50 mcg/mL) and mean trough concentration, thought to be an indicator of drug accumulation, 0.12 ± 0.05 mcg/mL (target range: 0.14–0.19 mcg/mL). No major bleeding or VTE events were noted during FPX administration.

Conclusion: A pharmacokinetic simulation permitting extrapolation of FPX dosing for VTE prophylaxis in patients with severe renal dysfunction from data in patients with mild dysfunction has been shown to be valid in a small population of sick elderly cancer patients by PK monitoring using a FPX -specific anti-Factor Xa assay, showing no drug accumulation over at least three doses (144 hrs) [cyl1] and the drug clinically safe as dosed.