Population pharmacokinetics of fondaparinux administered at prophylactic doses after major orthopaedic surgery in everyday practice

 

PDF Download Buy Article Permissions and Reprints

Summary

Fondaparinux is a synthetic antithrombotic agent with specific anti-factor Xa activity. A population pharmacokinetic model of fondaparinux, based on data obtained in patients included in phase II/III trials, has been described. However, the validity of this model in everyday practice needed to be confirmed. This study was a multicenter, prospective cohort study in consecutive orthopaedic patients treated with 2.5 mg of fondaparinux. Anti-Xa activities were recorded in 809 patients. Population parameters and inter-individual variability were estimated using NONMEM VI software. A two-compartment model with first-order absorption best described fondaparinux pharmacokinetics. Covariates partly explaining inter-individual variability were body weight, age and creatinine clearance estimated by the simplified Modification of Diet in Renal Disease formula (MDRD). A body weight less than 50 kg and moderate renal failure increased drug exposure. Although the population pharmacokinetic model of fondaparinux was described, this one requires to be validated in everyday practice.

^* A list of investigators is given in the Appendix.

• References

• 1 Geerts WH, Bergqvist D, Pineo GF. et al. American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 381-453.
  CrossrefPubMedGoogle Scholar
• 2 Turpie A, Bauer K, Eriksson B. et al. Steering Committees of the Pentasaccharide Orthopedic Prophylaxis Studies. Efficacy and safety of fondaparinux in major orthopedic surgery according to the timing of its first administration. Thromb Hae-most 2003; 90: 364-366.
  Article in Thieme ConnectPubMedGoogle Scholar
• 3 Donat F, Duret JP, Santoni A. et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet 2002; 41: 1-9.
  PubMedGoogle Scholar
• 4 Turpie AG, Lensing AW, Fuji T. et al. Pharmacokinetic and clinical data supporting the use of fondaparinux 1.5 mg once daily in the prevention of venous throm-boembolism in renally impaired patients. Blood Coagul Fibrinolysis 2009; 20: 114-121.
  CrossrefPubMedGoogle Scholar
• 5 Eriksson I B, Bauer KA, Lassen MR. et al. Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hipfracture surgery. N Engl J Med 2001; 345: 1298-1304.
  CrossrefPubMedGoogle Scholar
• 6 Turpie AG, Gallus AS, Hoek JA. Pentasaccharide Investigators. A synthetic pentas-accharide for the prevention of deepvein thrombosis after total hip replacement. N Engl J Med 2001; 344: 619-625.
  CrossrefPubMedGoogle Scholar
• 7 Turpie AG, Bauer KA, Eriksson I B. et al. PENTATHALON 2000 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002; 359: 1721-1726.
  CrossrefPubMedGoogle Scholar
• 8 Rosencher N, Vielpeau C, Emmerich J. et al. ESCORTE group. Venous thromboembolism and mortality after hip fracture surgery: the ESCORTE study. J Thromb Haemost 2005; 03: 2006-2014.
  CrossrefPubMedGoogle Scholar
• 9 Samama CM, Ravaud P, Parent F. et al. Epidemiology of venous thromboembolism after lower limb arthroplasty: the FOTO study. J Thromb Haemost 2007; 05: 2360-2367.
  CrossrefPubMedGoogle Scholar
• 10 Mueck W, Borris LC, Dahl OE. et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Hae-most. 2008; 100: 453-461.
  Article in Thieme ConnectPubMedGoogle Scholar
• 11 Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010; 103: 572-585.
  Article in Thieme ConnectPubMedGoogle Scholar
• 12 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41.
  CrossrefPubMedGoogle Scholar
• 13 Levey AS, Bosch JP, Lewis JB. et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461-470.
  CrossrefPubMedGoogle Scholar
• 14 Laroche L, Charmes JP, Marcheix A. et al. Estimation of glomerular filtration rate in the elderly: Cockcroft –Gault formula versus modification of diet in renal disease formula. Pharmacother 2006; 26: 1041-1046.
  CrossrefPubMedGoogle Scholar
• 15 Bara L, Planes A, Samama MM. Occurrence of thrombosis and haemorrhage, relationship with anti-Xa, anti-IIa activities, and D-dimer plasma levels in patients receiving a low molecular weight heparin, enoxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery. Br J Haematol 1999; 104: 230-240.
  CrossrefPubMedGoogle Scholar
• 16 Beal SL, Sheiner LB. Estimating population kinetics. Crit Rev Biomed Eng 1982; 08: 195-222.
  PubMedGoogle Scholar
• 17 Sheiner LB, Grasela TH. An introduction to mixed effect modelling: concepts, definitions and justification. J Pharmacokinet Biopharm 1991; 19: 11-24.
  CrossrefPubMedGoogle Scholar
• 18 Wählby U, Jonsson EN, Karlsson MO. Assessment of actual significance levels for covariate effects in NONMEM. J Pharmacokinet Pharmacodyn 2001; 28: 231-252.
  CrossrefPubMedGoogle Scholar
• 19 Jadhav PR, Gobburu JV. A new equivalence based metric for predictive check to qualify mixed-effects models. AAPS J 2005; 07: 523-523.
  CrossrefPubMedGoogle Scholar
• 20 Brendel K, Dartois C, Comets E. et al. Are population pharmacokinetic and/or pharmacodynamic models adequately evaluated? A survey of the literature from 2002 to 2004. Clin Pharmacokinet 2007; 46: 221-234.
  CrossrefPubMedGoogle Scholar
• 21 Sheiner LB, Beal SL. Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 1981; 09: 503-512.
  CrossrefPubMedGoogle Scholar
• 22 National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: 1-266.
  CrossrefPubMedGoogle Scholar
• 23 Fehrman-Ekholm I, Skeppholm L. Renal function in the elderly (>70 years old) measured by means of iohexol clearance, serum creatinine, serum urea and estimated clearance. Scand J Urol Nephrol 2004; 38: 73-77.
  CrossrefPubMedGoogle Scholar
• 24 Berges A, Laporte S, Epinat M. et al. Anti-factor Xa activity of enoxaparin administered at prophylactic dosage to patients over 75 years old. Br J Clin Pharmacol 2007; 64: 428-438.
  CrossrefPubMedGoogle Scholar
• 25 Arixtra. Fondaparinux sodium. Summary of product characteristics. European Agency for the Evaluation of Medicinal Products (EMEA). Available from. http://www.ema.europa.eu/humandocs/PDFs/EPAR/arixtra/011502en6.pdf Accessed January 15, 2010
  PubMedGoogle Scholar