title: Pharmacokinetics of fondaparinux 1.5 mg once daily in a real-world cohort of patients with renal impairment undergoing major orthopaedic surgery.
abstract: OBJECTIVE
  Fondaparinux, a selective activator factor X (factor Xa) inhibitor, is effective and safe for preventing venous thromboembolism after major orthopaedic surgery (MOS) at the once-daily subcutaneous dose of 2.5 mg. As the drug is mainly eliminated by the kidneys, a reduced dosage (1.5 mg once daily) was developed for patients with renal impairment.
  
  
  METHODS
  We studied the pharmacokinetics (PK) of this dosage regimen using data from a real-world cohort of 442 patients with renal impairment (creatinine clearance 20-50 ml/min) undergoing MOS. Data were analysed using NON-linear Mixed Effect Modelling software (NONMEM) software. Fondaparinux PK was modelled using a two-compartment model with first-order absorption.
  
  
  RESULTS
  This analysis confirmed the relationship between renal function and fondaparinux PK profiles. The mean predicted steady-state area under the plasma concentration time curve, peak and trough plasma concentrations of fondaparinux were lower by 15.6 %, 13.0 % and 10.3 %, respectively, in patients with renal impairment treated with 1.5 mg compared with patients with normal renal function treated with 2.5 mg (p < 0.01).
  
  
  CONCLUSIONS
  Although administration of 1.5 mg fondaparinux in patients with renal impairment resulted in a predicted exposure slightly lower than that achieved with 2.5 mg in patients with normal renal function, fondaparinux 1.5 mg is a valuable thromboprophylactic option in MOS patients with renal impairment who are at risk of bleeding.
authors.affiliation: Thrombosis Research Group (EA 3065), University Jean Monnet, 42023, Saint-Etienne, France. xavier.delavenne@chu-st-etienne.fr
authors.forename: Xavier
authors.initials: X
authors.lastname: Delavenne
authors.forename: Paul
authors.initials: P
authors.lastname: Zufferey
authors.forename: Philippe
authors.initials: P
authors.lastname: Nguyen
authors.forename: Nadia
authors.initials: N
authors.lastname: Rosencher
authors.forename: Charles-Marc
authors.initials: CM
authors.lastname: Samama
authors.forename: Céline
authors.initials: C
authors.lastname: Bazzoli
authors.forename: Patrick
authors.initials: P
authors.lastname: Mismetti
authors.forename: Silvy
authors.initials: S
authors.lastname: Laporte
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015331:Cohort Studies; D004334:Drug Administration Schedule; D065427:Factor Xa Inhibitors; D005260:Female; D000077425:Fondaparinux; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019637:Orthopedic Procedures / Q000379:methods*; D011134:Polysaccharides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000097:blood / Q000378:metabolism*; D054556:Venous Thromboembolism / Q000517:prevention & control
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011134:Polysaccharides; D000077425:Fondaparinux