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J Thromb Haemost. 2018 Nov;16(11):2196-2207. doi: 10.1111/jth.14292. Epub 2018 Oct 28.

Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery.

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Hospital Pharmacy-Clinical Pharmacology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
Department of Pediatric Hematology, Erasmus University Medical Center - Sophia Children's Hospital Rotterdam, Rotterdam, the Netherlands.
Great Ormond Street Haemophilia Centre, Great Ormond Street Hospital for Children NHS Trust, London, UK.
Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UK.
Netherlands Hemophilia Patient Society (NVHP), Nijkerk, the Netherlands.
Department of Haematology, The Royal London Hospital Barts Health NHS Trust, London, UK.
Oxford Haemophilia and Thrombosis Centre, Oxford University Hospitals, Churchill Hospital, Oxford, UK.
Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Department of Pediatric Hematology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
Department of Plasma Proteins, Sanquin Research, Amsterdam, the Netherlands.
Department of Hematology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.


Essentials Factor IX (FIX) dosing using body weight frequently results in under and overdosing during surgery. We aimed to establish a population pharmacokinetic (PK) model describing the perioperative FIX levels. Population PK parameter values for clearance and V1 were 284 mL h-170 kg-1 and 5450 mL70 kg-1. Perioperative PK parameters differ from those during non-surgical prophylactic treatment. SUMMARY: 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 NONMEM. 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-170 kg-1 (18%); V1, 5450 mL70 kg-1 (19%); Q2, 110 mL h-170 kg-1; V2, 4800 mL70 kg-1; Q3, 1610 mL h-170 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.


coagulation factor IX; coagulation factor concentrates; hemophilia B; pharmacokinetics; surgery


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