• Magali Bolon-larger Evaluation du Médicament
  • FranÇoise Bressolle Laboratoire de Pharmacocinétique Clinique
  • Yoann Chevalier CHU de Lyon
  • Valerie Chamouard CHU de Lyon
  • Roberto Gomeni GlaxoSmithKline, King of Prussia
  • Roselyne Boulieu University Lyon1, Faculty of Pharmacy


Objective: to develop a population pharmacokinetic model taking into account blood losses during and after orthopedic surgery in adult hemophilia A patients receiving infusion of coagulation factor VIII, and to evaluate the influence of potential covariates.

Methods: Factor VIII pharmacokinetic parameters were calculated from 24 patients. Among them, 7 were HIV+. The observations were analyzed with the mixed-effects compartment pharmacokinetic package NONMEM and the first-order conditional estimation method. To evaluate the stability and robustness of the final model the bootstrap method was used.

Results: During the model-building process, central volume of distribution (V1) was related to body weight (P = 0.0263) and viral status (P = 0.0078). Moreover, the peripheral volume of distribution was related to body weight (P=0.0362). In the final model, only the viral status was significant for V1 when compared with the base model. Posterior predictive checks and robustness analysis showed that the model adequately described the pharmacokinetic parameters. The HIV covariate accounted for 29.8% of the unexplained variation across patients for V1. V1 increased by 33.3% in HIV+ patients compared to HIV- patients.

Conclusion: A population pharmacokinetic model taking into account blood losses during and after orthopedic surgery was developed. The 33.3% increase in V1 observed in HIV+ patients explained the need for higher doses in these patients.


Keywords: Factor VIII, Population pharmacokinetics, Hemophilia A, Orthopedic surgery


Download data is not yet available.


1. Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, et al. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984;312:342–7.
2. Truett MA, Blacher R, Burke RL, Caput D, Chu C, Dina D, et al. Characterization of the polypeptide composition of human factor VIII: C and the nucleotide sequence and expression of the human kidney cDNA. DNA 1985;4:333–49.
3. Australian Haemophilia Centre Directors’Organisation. Guideline for the management of hemophilia A patients undergoing surgical procedures has been published; 2010.
4. Björkman S, Berntorp E. Pharmacokinetics of coagulation factors. Clin Pharmacokinet 2001;40:815-32.
5. Nilsson IM, Berntorp E, Lofqvist T, Pettersson H. Twenty-five years experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992;232:25–32.
6. Aledort LM, Haschemeyer RH. Pettersson H and the Orthopaedic Outcomes Study Group. A longitudinal study of orthopaedic outcomes for severe factor VIII deficient haemophiliacs. J Intern Med 1994;236:391–9.
7. Fischer K, Van der Bon JG, Molho P, Negrier C, Mauser-Bunschoten EP, Roosendaal G, et al. Prophylactic versus on-demand treatment strategies for severe haemophilia: a comparison of costs and long-termoutcomes. Haemophilia 2002;8:745–52.
8. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357:535–44.
9. Takedani H. Continuous infusion during total joint arthroplasty in Japanese hemophilia a patients: comparison study among two recombinants and one plasma-derived factor VIII. Haemophilia 2010;16:740-6.
10. Shapiro AD, Korth-Bradley J, Poon MC. Use of pharmacokinetics in the coagulation factor treatment of patients with haemophilia. Haemophilia 2005;11:571-82.
11. Messori A, Longo G, Morfini M, Donati-Cori G, Matucci M, Ruffo S. Individualization of factor VIII dosage. J Clin Hosp Pharm 1984;9:95-103.
12. Ruffo S, Messori A, Grasela TH, Longo G, Donati-Cori G, Matucci M, et al. A calculator program for clinical application of the Bayesian method of predicting plasma drug levels. Comput Programs Biomed 1985;19:167-77.
13. Ruffo S, Messori A, Longo G, Matucci M, Morfini M, Rossi-Ferrini P. A microcomputer program for individualizing factor VIII dosage in haemophilia patients undergoing major surgery. Comput Methods Programs Biomed 1986;23:37-46.
14. Matucci M, Messori A, Donati-Cori G, Longo G, Vannini S, Morfini M, et al. Kinetic evaluation of four factor VIII concentrates by model-independent methods. Scand J Haematol 1985;34:22-8.
15. Longo G, Matucci M, Messori A, Morfini M, Rossi-Ferrini P. Pharmacokinetics of a new heat-treated concentrate of factor VIII estimated by model-independent methods. Thromb Res 1986;42:471-6.
16. Morfini M, Mannucci PM, Longo G, Cinotti S, Messori A. Comparative evaluation of the pharmacokinetics of three monoclonal factor VIII concentrates. Thromb Res 1991;61:285-90.
17. Morfini M, Longo G, Messori A, Lee M, White G, Mannucci P. Pharmacokinetic properties of recombinant factor VIII compared with a monoclonally purified concentrate (Hemofil®M). Thromb Haemost 1992;68:433-5.
18. Messori A, Morfini M, Blomback M, Cinotti S, Longo G, Schimpf K, et al. Pharmacokinetics of two pasteurized factor VIII concentrates by different and multicenter assays of factor VIII activity. Thromb Res 1992;65:699-708.
19. Björkman S, Carlsson M, Berntorp E, Stenberg P. Pharmacokinetics of factor VIII in humans. Clin Pharmacokinet 1992;22:385-95.
20. Lee C, Barrowcliffe T, Bray G, Gomperts E, Hubbard A, Kemball-Cook G, et al. Pharmacokinetic in vivo comparison using 1-stage and chromogenic substrate assays with two formulations of haemophil-M. Thromb Haemostasis 1996;76:950-6.
21. Fijnvandraat K, Berntorp E, Ten Cate JW, Johnsson H, Peters M, Savidge G, et al. Recombinant, B-domain deleted factor VIII: pharmacokinetics and initial safety aspects in haemophilia A patients. Thromb Haemostasis 1997;77:298-302.
22. Rochat C, Mc Fayden ML, Schwyzer R, Gillham A, Cruickshank A. Continuous infusion of intermediate-purity factor VIII in haemophilia A patients undergoing elective surgery. Haemophilia 1999;5:181-6.
23. Morfini M. Comparative pharmacokinetic studies in haemophilia. Haemophilia 2002;8 Suppl 2:30-3.
24. Morfini M. Pharmacokinetics of factor VIII and factor IX. Haemophilia 2003;9 Suppl 1:94–100.
25. Ahnström J, Berntorp E, Lindvall K, Björkman S. A 6-year follow-up of dosing, coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophilia. Haemophilia 2004;10:689–97.
26. Collins PW, Blanchette VS, Fischer K, Björkman S, Oh M, Fritsch S, et al. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemostasis 2009;7:413-20.
27. Björkman S, Blanchette VS, Fischer K, Oh M, Spotts G, Schroth P, et al. Comparative pharmacokinetics of plasma-and albumine-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring. J Thromb Haemostasis 2010;8:730-6.
28. Dmoszynska A, Hellmann A, Baglin T, O’Shaugnessy D, Trelinski J, Kuliczowski K, et al. Pharmacokinetics of Optivate(®), a high-purity concentrate of factor VIII with von Willebrand factor, in patients with severe haemophilia A. Haemophilia 2011;17:185-90.
29. Blanchette VS, Shapiro AD, Liesner RJ, Hernandez Navarro F, Warrier I, Schroth PC, et al. Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients. J Thromb Haemostasis 2008;6:1319-26.
30. Björkman S, Oh M, Spotts G, Schroth P, Fritsch S, Ewenstein BM, et al. Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood 2012;119:612-8.
31. Longo G, Messori A, Morfini M, Baudo F, Ciavarella N, Cinotti S, et al. Evaluation of factor VIII pharmacokinetics in hemophilia-A subjects undergoing surgery and description of a nomogram for dosing calculations. Am J Hematol 1989;30:140-9.
32. Bolon-Larger M, Chamouard V, Bressolle F, Boulieu R. A limited sampling strategy for estimating individual pharmacokinetic parameters of coagulation factor VIII in patients with haemophilia A. Ther Drug Monit 2007;28:20–6.
33. Karafoulidou A, Suarez E, Anastasopoulou I, Katsarou O, Kouramba A, Kotsi P, et al. Population pharmacokinetics of recombinant factor VIII: C (ReFacto) in adult HIV-negative and HIV-positive haemophilia patients. Eur J Clin Pharmacol 2009;65:1121-30.
34. Björkman S, Folkesson A, Jönsson S. Pharmacokinetics and dose requirements of factor VIII over the age range 3-74 years: a population analysis based on 50 patients with long-term prophylactic treatment for haemophilia A. Eur J Clin Pharmacol 2009;65:89-98.
35. Björkman S. Limited blood sampling for pharmacokinetic dose tailoring of FVIII in the prophylactic treatment of haemophilia A. Haemophilia 2010;16:597-605.
36. Beal SL, LB Sheiner. NONMEM User's Guide. San Francisco, USA: University of California at San Francisco; 1994.
37. Rosencher N, Kerkkamp HEM, Macheras G, Munuera LM, Menichella G, Barton DM, et al. Orthopedic surgery transfusion hemoglobin European overview (OSTHEO) study: blood management in elective knee and hip arthroplasty in Europe. Transfus 2003;43:459-69.
38. Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit--a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed 2005;79:241-57.
39. Jonsson EN, Karlsson MO. Xpose--an S-PLUS based population pharmacokinetic/ pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 1999;58:51-64.
40. Efron B, Tibshirani R. Bootstrap methods for standard errors, confidence intervals, and other measures of statistical accuracy. Stat Sci 1986;1:54-77.
41. Report of a joint WHO/WFH/ISTH Meeting, London, UK, 11–13 February. Human Genetics Programme, Management of Noncommunicable Diseases, World Health Organization. Delivery of Treatment for Haemophilia; 2002.
42. Tumbarello M, Tacconelli E, Donati KG, Citton R, Leone F, Spanu T, et al. HIV-associated bacteremia: how it has changed in the highly active antiretroviral therapy (HAART) era. J Acquired Immune Defic Syndr 2010;23:145-51.
43. Hay CR, Doughty HI, Savidge GF. Continuous infusion of factor VIII for surgery and major bleeding. Blood Coagulation Fibrinolysis 1996;7 Suppl 1:15-9.
379 Views | 1051 Downloads
How to Cite
Bolon-larger, M., F. Bressolle, Y. Chevalier, V. Chamouard, R. Gomeni, and R. Boulieu. “POPULATION PHARMACOKINETICS OF CONTINUOUS INFUSION OF FACTOR VIII IN HEMOPHILIA-A PATIENTS UNDERGOING ORTHOPEDIC SURGERY”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 7, no. 2, Dec. 2014, pp. 109-14, https://innovareacademics.in/journals/index.php/ijpps/article/view/1940.
Original Article(s)