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Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery

Preijers, T., Hazendonk, H.C.A.M., Liesner, R., Chowdary, P., Driessens, M.H.E., Hart, D., Keeling, D., Laros-van Gorkom, B.A.P., van der Meer, F.J.M., Meijer, K., Fijnvandraat, K., Leebeek, F.W.G., Collins, Peter W., Cnossen, M.H. and Mathôt, R.A.A. 2018. Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery. Journal of Thrombosis and Haemostatis 16 (11) , pp. 2196-2207. 10.1111/jth.14292

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Wiley-Blackwell
ISSN: 1538-7933
Date of First Compliant Deposit: 18 September 2018
Date of Acceptance: 19 August 2018
Last Modified: 17 Oct 2019 23:34

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