Population pharmacokinetic analysis of perioperative factor IX dosing in hemophilia B
T. Preijers (1), H.C.A.M. Hazendonk (2), R. Liesner (3), P. Chowdary (4), M.H.E. Driessens (5), D. Hart (6), D. Keeling (7), B.A.P. Laros-van Gorkom (8), F.J.M. van der Meer (9), K. Meijer (10), K. Fijnvandraat (11), F.W.G. Leebeek (12), P.W. Collins (13), M.H. Cnossen (2), R.A.A. Mathôt (1) for the “OPTI-CLOT” study group.
(1) Hospital Pharmacy-Clinical Pharmacology, Academic Medical Center Amsterdam, the Netherlands., (2) Department of Pediatric Hematology, Erasmus University Medical Center - Sophia Children’s Hospital Rotterdam, Rotterdam, the Netherlands., (3) Great Ormond Street Haemophilia Centre, Great Ormond Street Hospital for Children NHS trust, London, United Kingdom., (4) Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, United Kingdom., (5) Netherlands Hemophilia Patient Society (NVHP), Nijkerk, the Netherlands., (6) Department of Haematology, The Royal London Hospital Barts Health NHS Trust, London, United Kingdom., (7) Oxford Haemophilia and Thrombosis Centre, Oxford University Hospitals, Churchill Hospital, Oxford, United Kingdom., (8) Department of Hematology, Radboud university medical center, Nijmegen, the Netherlands., (9) Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands., (10) University of Groningen, Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands., (11) Department of Pediatric Hematology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands., (12) Department of Hematology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands., (13) Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Objectives: To construct a population PK model using retrospective clotting factor IX plasma levels (FIX:C) from hemophilia B patients undergoing a surgical procedure.
Methods: Retrospective data of 118 hemophilia B patients, with a median (range) age of 40.1 years (0.15–90.45) and a body weight of 81.5 kg (5.3-132), undergoing 255 surgical procedures, was available from ten hemophilia treatment centers in the Netherlands (n=25 patients) and the United Kingdom (n=93 patients). From this population, 79% of the patients administered recombinant FIX products, 31% received regular prophylactic treatment, 5% was known to have a history with anti-drug antibodies, 72% was diagnosed with severe hemophilia (<0.01IU/mL endogenous FIX:C) and 36 patients were below 18 years. Non-linear mixed effect modeling was performed using FOCE+I in NONMEM v7.3 [1]. A compartment initialization method was used in case pre-dose measurements of FIX:C were available. For patients with an endogenous baseline level, this measurement was subtracted from each observation. Covariate relationships, such as patient characteristics and clinical features, were evaluated to explain inter-patient variability (IIV). Model diagnosis was performed using GOF plots in Xpose v4.5.3 [2] and VPCs.
Results: FIX:C versus time profiles, comprising 1417 FIX:C observations, were adequately described using a three-compartment model. PK parameters were allometrically scaled using the ¾ power-model for CL and 1 for V. Population PK parameter estimates and IIV (%) were: CL: 293 mL/h/70kg (21.1%), V1: 5010 mL/70kg (16.8%), Q2:102 mL/h/70kg, V2: 4780 mL/70kg, Q3: 1310 mL/h/70kg, V3: 2080 mL/70kg. With rising age, CL and V1 decreased 0.8% and 1.2% per year, respectively, until the age of 32 years. Compared to the United Kingdom, V1 was 14.5% higher for patients treated in the Netherlands. Furthermore, an increase of 16.4% and 22.1% for CL and V1, respectively, was associated to the use a recombinant product. A complication, such as an infection or bleeding, during the surgical procedure resulted in 16.4% increase of CL.
Conclusions: Measured peri-operative FIX:C were described adequately by the established population PK model. Estimated population PK parameters were different from those reported for prophylactic treatment. This model will be used in a prospective clinical trial to perform PK-guided dosing of hemophilia B patients undergoing a surgical procedure.
References:
[1] Beal S, Sheiner LB, Boeckmann AJ, Bauer RJ. NONMEM User Guides. 1989-2011; Icon Development Solutions, Ellicott City, Maryland, USA.
[2] Jonsson EN, Karlsson MO. Xpose--an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Computer methods and programs in biomedicine. 1999;58(1):51-64.