Clinical outcomes in hemophilia A patients undergoing tailoring of prophylaxis based on population-based pharmacokinetic dosing

Published:November 15, 2018DOI:https://doi.org/10.1016/j.thromres.2018.11.017

      Highlights

      • PK based tailoring of prophylaxis in hemophilia was proposed to 39 Japanese patients.
      • Dose increase, infusion frequency reduction, or switch to extended half-life concentrates can explain.
      • Adherence to treatment improved or did not change.
      • The annualized bleeding improved or remained unchanged, and was associated with time spent above 0.01 or 0.05 IU/mL.

      Abstract

      Introduction

      Standard prophylaxis dosing based on bodyweight may result in over- or under-dosing due to interpatient variability. Adopting individual pharmacokinetic (PK) based tailoring may improve adherence to treatment guideline, and consequently clinical outcomes. Here we report clinical observations performed across the adoption of individual PK based tailoring in a single center in Japan.

      Methods

      An individual PK study on sparse samples was modeled on myPKFiT or WAPPS-Hemo, depending on concentrate, and used to optimize treatment regimens. Adherence to prophylaxis and bleeding rate were calculated from patient diaries. Radiological joint scores were used to assess arthropathy, and SPSS to perform all the analyses.

      Results

      Thirty-nine patients underwent PK profiling, and 20 required and accepted a modification of their treatment (8 increases in dose, 5 reductions in frequency, 5 switches to extended half-life (EHL)). Adherence to prophylaxis remained the same in those increasing the dose, whilst increased in all the other groups. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AjBR) decreased in all the groups but reached statistical significance only in those switched to EHL and showed a larger reduction in those patients without baseline arthropathy. Longer time spent above a 1% or 5% threshold was associated with a decrease in the ABR/AjBR.

      Conclusions

      Our study results suggest that PopPK based tailoring supported changing treatment regimen in nearly half of the patients, and may have contributed to an improvement in the adherence and a reduction in the ABR/AjBR.

      Abbreviations:

      PK (pharmacokinetic), SHL (standard half-life products), EHL (extended half-life products), rFVIII (recombinant factor VIII), FVIII:C (FVIII activity), ABR (annualized bleeding rate), AjBR (annualized joint bleeding rate)

      Keywords

      To read this article in full you will need to make a payment
      Subscribe to Thrombosis Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Collins P.W.
        • Fischer K.
        • Morfini M.
        • et al.
        Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia.
        Haemophilia. 2011; 17: 2-10
        • Croteau S.E.
        • Callaghan M.U.
        • Davis J.
        • et al.
        Focusing in on use of pharmacokinetic profiles in routine hemophilia care.
        Res. Pract. Thromb. Haemost. 2018; 27: 607-614
        • Lee M.
        • Morfini M.
        • Schulman S.
        • et al.
        The Design and Analysis of Pharmacokinetic Studies of Coagulation Factors.
        2001: 1-9 (Available from:)
        • Iorio A.
        • Keepanasseril A.
        • Foster G.
        • et al.
        Development of a web-accessible population pharmacokinetic service—hemophilia (WAPPS-Hemo): study protocol.
        JMIR Res. Protoc. 2016; 5 ([Internet]. Available from:): e239
        • Bjorkman S.
        Limited blood sampling for pharmacokinetic dose tailoring of FVIII in the prophylactic treatment of haemophilia A.
        Haemophilia. 2010; 16: 597-605
        • Blanchette V.S.
        • Key N.S.
        • Ljung L.R.
        • et al.
        Definitions in hemophilia: communication from the SSC of the ISTH.
        J. Thromb. Haemost. 2014; 12: 1935-1939
        • Arnold W.
        • Hilgartner M.
        Hemophilic arthropathy. Current concepts of pathogenesis and management.
        J. Bone Joint Surg. Am. 1977; 59: 287-305
        • García-Dasí M.
        • Aznar J.A.
        • Jiménez-Yuste V.
        • et al.
        Adherence to prophylaxis and quality of life in children and adolescents with severe haemophilia A.
        Haemophilia. 2015; 21: 458-464
        • Schrijvers L.S.H.
        • Beijlevelt-van der Zande M.
        • Peters M.
        • et al.
        Adherence to prophylaxis and bleeding outcome in haemophilia: a multicentre study.
        Br. J. Haematol. 2016; 174: 454-460
        • Pérez-Robles T.
        • Romero-Garrido José A.
        • Rodriguez-Merchan E.C.
        • et al.
        Objective quantification of adherence to prophylaxis in haemophilia patients aged 12 to 25 years and its potential association with bleeding episodes.
        Thromb. Res. 2016; 143 ([Internet] Elsevier Ltd.. Available from): 22-27