Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery

Opti-Clot Study Grp, Nov-2018, In : JOURNAL OF THROMBOSIS AND HAEMOSTASIS. 16, 11, p. 2196-2207 12 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Opti-Clot Study Grp

Background: Hemophilia B is a bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). In the perioperative setting, patients receive FIX concentrates to ensure hemostasis. Although FIX is usually dosed according to bodyweight, under- and overdosing occurs frequently during surgery. Aim: The objective was to quantify and explain the interpatient variability of perioperatively administered plasma-derived (pd) and recombinant (r) FIX concentrates. 

Methods: Data were collected from 118 patients (median age, 40 years [range, 0.2-90]; weight, 79 kg [range, 5.3-132]) with moderate (28%) or severe hemophilia B (72%), undergoing 255 surgical procedures. Population pharmacokinetic (PK) parameters were estimated using nonlinear mixed-effect modeling in NON-MEM. 

Results: Measured perioperative FIX level vs. time profiles were adequately described using a three-compartment PK model. For a typical 34-year-old patient receiving rFIX, clearance (CL), intercompartmental clearance (Q2, Q3), distribution volume of the central compartment (V1) and peripheral compartments (V2, V3) plus interpatient variability (%CV) were: CL, 284 mL h(-1)70 kg(-1) (18%); V1, 5450 mL70 kg(-1) (19%); Q2, 110 mL h(-1)70 kg(-1); V2, 4800 mL70 kg(-1); Q3, 1610 mL h(-1)70 kg(-1); V3, 2040 mL70 kg(-1). From 0.2 years, CL and V1 decreased 0.89% and 1.15% per year, respectively, until the age of 34 years. Patients receiving pdFIX exhibited a lower CL (11%) and V1 (17%) than patients receiving rFIX. Interpatient variability was successfully quantified and explained. 

Conclusions: The estimated perioperative PK parameters of both pdFIX and rFIX are different from those reported for prophylactic treatment. The developed model may be used to apply PK-guided dosing of FIX concentrates during surgery.

Original languageEnglish
Pages (from-to)2196-2207
Number of pages12
Issue number11
Publication statusPublished - Nov-2018


  • coagulation factor concentrates, coagulation factor IX, hemophilia B, pharmacokinetics, surgery, RECOMBINANT FACTOR-IX, MIXED-EFFECTS MODELS, COAGULATION-FACTORS, PROPHYLAXIS, MANAGEMENT, FUNDAMENTALS, SIMULATION, THERAPY, AGE

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