Physiologically-based pharmacokinetic modelling of recombinant factor IX Fc fusion protein (rFIXFc) and recombinant FIX (rFIX) to characterize extravasation and binding to type IV collagen
M.E. Cloesmeijer (1), E. Sjögren (2)(3), P.J. Lenting (4), M.H. Cnossen (5) and R.A.A. Mathôt (1)
(1) Amsterdam UMC location University of Amsterdam, The Netherlands, (2) Uppsala University, Sweden, (3) Pharmetheus, Sweden, (4) Inserm U.1176 & Université Paris-Saclay, France, (5) Erasmus MC Sophia Children’s Hospital, University Medical Center Rotterdam, The Netherlands
Introduction: Hemophilia B (HB) is caused by a deficiency of coagulation factor IX (FIX), which results in bleeding, typically in joints and muscles. To prevent bleeding, patients with severe HB receive prophylactic therapy with intravenous doses of FIX concentrate, thereby maintaining a FIX trough level >1 IU/dL.[1] Recently, chemically modified FIX concentrates have been developed with extended terminal half-life (EHL-concentrates), such as recombinant FIX coupled to the human IgG1 Fc domain (rFIXFc).[2] Standard half-life (SHL) FIX concentrates, such as recombinant FIX (rFIX) are generally administered two-times a week, whereas EHL-concentrates usually require only once weekly dosing.
rFIXFc has a rapid distribution phase, which is probably due to binding to type IV collagen (COL4) in the extravascular space.[3] The ratio of the amount FIX bound extravascular and the amount in plasma is approximately 17-20.[3.4] The FIX levels in the extravascular space seem crucial, as they exhibit hemostatic effects despite no measurable or low FIX levels in plasma. Currently, empirical population pharmacokinetic (PK) models have been developed for FIX concentrates[5]. These models describe only plasma FIX levels over time, since FIX levels are measured in the blood, but not in the extravascular space.
Objectives:
- Develop a PBPK model of rFIXFc in adults HB patients
- Quantify the binding of rFIXFc to COL4
- Investigate the predictive performance of the PBPK model of rFIXFc for rFIX
Methods:
The PBPK model for therapeutic proteins in PK-Sim (version 11 – build 150, Open Systems Pharmacology) was used to develop the rFIXFc PBPK model. Model parameter identification was achieved using the Levenberg-Marquardt algorithm in PK-Sim. Physicochemical properties and clinical observations were obtained from literature. Clinical rFIXFc observations were obtained from the EMA assessment report. Patients received an intravenous dose of 50 IU/kg (approximately 0.6 mg/kg) rFIXFc. COL4 is located in the extravascular space and vascular endothelial cells. The binding of rFIXFc to COL4 in the extravascular space was quantified to account for the rapid distribution phase and to describe the concentration of rFIXFc to COL4 in the extravascular space. To model the degradation of FIX in the plasma, an enzyme was added to the model to account for the protease activity. FcRn recycling was calibrated on the observational data by estimating the FcRn dissociation constant (Kd). After developing the model for rFIXFc, the FcRn recycling pathway was disabled to investigate the predictive performance of the rFIXFc model for the SHL-concentrate rFIX in patients receiving 55 IU/kg rFIX (approximately 0.3 mg/kg) by comparing to observed rFIX plasma levels by Suzuki et al.[6]
Results: Model predictions for rFIXFc were within two-fold error of the observed data (total residual error = 0.08). At t=0.10, 24, 96 and 240h a FIX plasma level of 72.0, 22.7, 7.81, 3.20 nM (approximately 47, 15, 5.1, 2.1 IU/dL) was predicted. The total concentration of rFIXFc to COL4 in the extravascular space was approximately 14 times higher compared to the concentration in plasma of FIX. The highest concentrations of rFIXFc to the extravascular COL4 was found in well perfused organs such as spleen, kidney and lungs, which seems consistent with previous reported literature of rFIX, rFIXFc and FIX with albumin.[7,8]
In the final model of rFIXFc, the Kd binding was disabled to investigate the predictive performance for rFIX. At t=0.25, 24, 48 and 72h, a FIX plasma level of 53.3, 7.74, 3.89 and 2.58 nM (approximately 36, 5.2, 2.6 and 1.7 IU/dL) was predicted. The PBPK model is also able to adequately predict rFIX levels, when comparing the predictions to the median rFIX observations.[6]
Conclusions: The developed PBPK model adequately predicts the plasma profiles of rFIXFc and rFIX and the binding of both concentrates to COL4 is quantified. Model predictions clearly display a higher concentration of FIX to COL4 in the extravascular space when compared to the plasma, which may highlight the importance of FIX in the extravascular space to prevent bleedings in the presence of lower FIX plasma levels.
References:
[1] Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020;26(S6):1-158.
[2] Graf L. Extended Half-Life Factor VIII and Factor IX Preparations. Transfus Med Hemotherapy. 2018;45(2):86-91.
[3] Stafford DW. Extravascular FIX and coagulation. Thromb J. 2016;14(Suppl 1).
[4] Mann DM, Stafford KA, Poon MC, Matino D, Stafford DW. The Function of extravascular coagulation factor IX in haemostasis. Haemophilia. 2021;27(3):332-339.
[5] Preijers T, Bukkems L, van Spengler M, Leebeek F, Cnossen M, Mathôt R. In silico comparison of pharmacokinetic properties of three extended half-life factor IX concentrates. Eur J Clin Pharmacol. 2021;77(8):1193-1200.
[6] Suzuki A, Tomono Y, Korth-Bradley JM. Population pharmacokinetic modelling of factor IX activity after administration of recombinant factor IX in patients with haemophilia B. Haemophilia. 2016;22(5):e359-e366.
[7] Salas J, Van Der Flier A, Hong VP, et al. Extravascular Distribution of Conventional and Ehl FIX Products Using In Vivo SPECT Imaging Analysis in Hemophilia B Mice. Blood. 2017;130(Suppl 1):1061 LP - 1061.
[8] Herzog E, Harris S, Henson C, et al. Biodistribution of the recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in rats. Thromb Res. 2014;133(5):900-907.
