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CC BY-NC-ND 4.0 · Thromb Haemost 2019; 119(03): 368-376
DOI: 10.1055/s-0039-1677700
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Impact of Adopting Population Pharmacokinetics for Tailoring Prophylaxis in Haemophilia A Patients: A Historically Controlled Observational Study

Michaela Stemberger
1   Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
2   Abteilung für Transfusionsmedizin, Zelltherapeutika und Hämostaseologie, Klinikum der Universität München, Munich, Germany
,
Felix Kallenbach
2   Abteilung für Transfusionsmedizin, Zelltherapeutika und Hämostaseologie, Klinikum der Universität München, Munich, Germany
,
Elisabeth Schmit
2   Abteilung für Transfusionsmedizin, Zelltherapeutika und Hämostaseologie, Klinikum der Universität München, Munich, Germany
,
Alanna McEneny-King
3   School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
,
Federico Germini
4   Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
5   Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
,
Cindy H. T. Yeung
4   Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
,
Andrea N. Edginton
3   School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
,
Sylvia von Mackensen
6   Institut und Poliklinik für Medizinische Psychologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
,
Karin Kurnik
7   Zentrum für Pädiatrische Hämostaseologie, Dr. von Haunersches Kinderspital, Klinikum der Universität München, Munich, Germany
,
Alfonso Iorio
4   Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
8   McMaster-Bayer Chair for Clinical Epidemiology Research in Bleeding Disorders, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
› Author Affiliations Funding The logistical operation of the study in Munich, including blood sampling and laboratory measurement for the PK studies, were sponsored by a research grant from Bayer Health Care and by Baxter Germany. The WAPPS-Hemo research program was solely supported by a B-CHERP grant, Association of the Hemophilia Centers Directors of Canada.
Further Information

Publication History

26 September 2018

09 December 2018

Publication Date:
27 January 2019 (online)

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Abstract

Background Performing individual pharmacokinetics (PK) studies in clinical practice can be simplified by adopting population PK-based profiling on limited post-infusion samples. The objective of this study was to assess the impact of population PK in tailoring prophylaxis in patients with haemophilia A.

Patients and Methods Individual weekly treatment plans were developed considering predicted plasma factor activity levels and patients' lifestyle. Patients were trained using a visual traffic-light scheme to help modulate their level of physical activity with respect to factor infusions timing. Annualized joint bleeding rate (ABJR), haemophilia-specific quality of life questionnaire for adults (Haemo-QoL-A) and factor utilization were measured for 12 months before and after tailoring, compared within patients and analysed separately for those previously on prophylaxis (P), situational prophylaxis (SP) or on-demand (OD).

Results Sixteen patients previously on P, 10 on SP and 10 on OD were enrolled in the study. The median (lower, upper quartile) ABJR changed from 2.0 (0, 4.0) to 0 (0, 1.6) for P (p = 0.003), from 2.0 (2.0, 13.6) to 3.0 (1.4, 7.2) for SP (p = 0.183) and from 16.0 (13.0, 25.0) to 2.3 (0, 5.0) for OD (p = 0.003). The Haemo-QoL-A total score improved for 58% of P, 50% of SP and 29% of OD patients. Factor utilization (IU/kg/patient/year) increased by 2,400 (121; 2,586) for P, 1,052 (308; 1,578) for SP and 2,086 (1,498; 2,576) for OD. One of 138 measurements demonstrated a factor activity level below the critical threshold of 0.03 IU/mL while the predicted level was above the threshold.

Conclusion Implementing tailored prophylaxis using a Bayesian forecasting approach in a routine clinical practice setting may improve haemophilia clinical outcomes.

Keywords

haemophilia - pharmacokinetics - prophylaxis - individualized - personalized

Authors' Contributions

M.S. and A.I. designed the study. M.S. coordinated the study. M.S. and K.K. conducted the study in Munich and collected the data. F.K. and E.S. performed the PK studies and laboratory assays. A.M.K. and A.N.E. performed the PopPK modelling and individual PopPK estimations. S.v.M. analysed the Haemo-QoL-A data. M.S., A.I., C.H.T.Y. and F.G. drafted the manuscript, analysed and interpreted the data. All the authors critically revised the manuscript and gave final approval to the current version.


Supplementary Material

 

  • References

  • 1 Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AK. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database Syst Rev 2011; (09) CD003429
    PubMedGoogle Scholar
  • 2 Srivastava A, Brewer AK, Mauser-Bunschoten EP. , et al; Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013; 19 (01) e1-e47
    CrossrefPubMedGoogle Scholar
  • 3 Iorio A. Using pharmacokinetics to individualize hemophilia therapy. Hematology (Am Soc Hematol Educ Program) 2017; 2017 (01) 595-604
    CrossrefPubMedGoogle Scholar
  • 4 McEneny-King A, Iorio A, Foster G, Edginton AN. The use of pharmacokinetics in dose individualization of factor VIII in the treatment of hemophilia A. Expert Opin Drug Metab Toxicol 2016; 12 (11) 1-9
    CrossrefPubMedGoogle Scholar
  • 5 Iorio A, McEneny-King A, Keepanasseril A, Foster G, Edginton A. What is the role for population pharmacokinetics in hemophilia?. Int J Pharmacokinet 2017; 2 (02) 125-136
    CrossrefPubMedGoogle Scholar
  • 6 Pasca S, Milan M, Sarolo L, Zanon E. PK-driven prophylaxis versus standard prophylaxis: when a tailored treatment may be a real and achievable cost-saving approach in children with severe hemophilia A. Thromb Res 2017; 157: 58-63
    CrossrefPubMedGoogle Scholar
  • 7 Álvarez-Román MT, Fernandez-Bello I, de la Corte-Rodríguez H. , et al. Experience of tailoring prophylaxis using factor VIII pharmacokinetic parameters estimated with myPKFiT® in patients with severe haemophilia A without inhibitors. Haemophilia 2017; 23 (01) e50-e54
    CrossrefPubMedGoogle Scholar
  • 8 Lee M, Morfini M, Schulman S, Ingerslev J. , and the Factor VIII/Factor IX Scientific and Standardization Committee of the International Society for Haemostasis and Thrombosis. The Design and Analysis of Pharmacokinetic Studies of Coagulation Factors. International Society on Thrombosis and Haemostasis; 2001. Available at: https://c.ymcdn.com/sites/www.isth.org/resource/group/d4a6f49a-f4ec-450f-9e0f-7be9f0c2ab2e/official_communications/fviiipharmaco.pdf . Accessed March 8, 2018
    PubMedGoogle Scholar
  • 9 Iorio A, Blanchette V, Blatny J, Collins P, Fischer K, Neufeld E. Estimating and interpreting the pharmacokinetic profiles of individual patients with hemophilia A or B using a population pharmacokinetic approach: communication from the SSC of the ISTH. J Thromb Haemost 2017; 15 (12) 2461-2465
    CrossrefPubMedGoogle Scholar
  • 10 Walton MK, Powers III JH, Hobart J. , et al; International Society for Pharmacoeconomics and Outcomes Research Task Force for Clinical Outcomes Assessment. Clinical outcome assessments: conceptual foundation-report of the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force. Value Health 2015; 18 (06) 741-752
    CrossrefPubMedGoogle Scholar
  • 11 Hilliard P, Funk S, Zourikian N. , et al. Hemophilia Joint Health Score reliability study. Haemophilia 2006; 12 (05) 518-525
    CrossrefPubMedGoogle Scholar
  • 12 Björkman S, Collins P. ; Project on Factor VI I I/Factor IX Pharmacokinetics of the Factor VIII/Factor IX Scientific and Standardization Committee of The Isth. Measurement of factor VIII pharmacokinetics in routine clinical practice. J Thromb Haemost 2013; 11 (01) 180-182
    PubMedGoogle Scholar
  • 13 McEneny-King A, Foster G, Iorio A, Edginton AN. Data analysis protocol for the development and evaluation of population pharmacokinetic models for incorporation into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo). JMIR Res Protoc 2016; 5 (04) e232
    CrossrefPubMedGoogle Scholar
  • 14 Iorio A, Keepanasseril A, Foster G. , et al; WAPPS-Hemo co-investigator network. Development of a Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): study protocol. JMIR Res Protoc 2016; 5 (04) e239
    CrossrefPubMedGoogle Scholar
  • 15 Rentz A, Flood E, Altisent C. , et al; Members of the HAEMO-QoL-A Steering Committee. Cross-cultural development and psychometric evaluation of a patient-reported health-related quality of life questionnaire for adults with haemophilia. Haemophilia 2008; 14 (05) 1023-1034
    CrossrefPubMedGoogle Scholar
  • 16 Valluri S, Flood E, Mink D, Bell J, Pocoski J, Sasane R. Determination of the minimal important difference (MID) of the haemophilia-specific quality of life questionnaire (Haemo-QOL-A) for adults with severe hemophilia A: PO-TU-233. Haemophilia 2012; 18: 180-181
    PubMedGoogle Scholar
  • 17 den Uijl IEM, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels. Haemophilia 2011; 17 (01) 41-44
    CrossrefPubMedGoogle Scholar
  • 18 Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1 (8476): 307-310
    PubMedGoogle Scholar
  • 19 Tagliaferri A, Feola G, Molinari AC. , et al; POTTER Study Group. Benefits of prophylaxis versus on-demand treatment in adolescents and adults with severe haemophilia A: the POTTER study. Thromb Haemost 2015; 114 (01) 35-45
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Manco-Johnson MJ, Kempton CL, Reding MT. , et al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART). J Thromb Haemost 2013; 11 (06) 1119-1127
    CrossrefPubMedGoogle Scholar
  • 21 Miners A. Revisiting the cost-effectiveness of primary prophylaxis with clotting factor for the treatment of severe haemophilia A. Haemophilia 2009; 15 (04) 881-887
    CrossrefPubMedGoogle Scholar
  • 22 Miners AH, Lee CA. Setting research priorities to improve cost-effectiveness estimations of primary prophylaxis with clotting factor for people with severe haemophilia. Haemophilia 2004; 10 (Suppl. 01) 58-62
    PubMedGoogle Scholar
  • 23 Miners AH. Economic evaluations of prophylaxis with clotting factor for people with severe haemophilia: why do the results vary so much?. Haemophilia 2013; 19 (02) 174-180
    CrossrefPubMedGoogle Scholar
  • 24 Fischer K, Steen Carlsson K, Petrini P. , et al. Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s. Blood 2013; 122 (07) 1129-1136
    CrossrefPubMedGoogle Scholar
  • 25 Pabinger I, Heistinger M, Muntean W. , et al. Treatment of haemophilia in Austria [in German]. Wien Klin Wochenschr 2015; 127 (03) (Suppl. 03) S115-S130
    CrossrefPubMedGoogle Scholar
  • 26 Nordic Hemophilia Council guideline working group, Armstrong E, Astermark J, et al. Nordic Hemophilia Guidelines; 2015. Available at: http://nordhemophilia.org/library/Files/PDF-skjol/NordicGuidelinesCongenitalHaemophilia_2017.pdf . Accessed March 7, 2018
    PubMedGoogle Scholar
  • 27 Dargaud Y, Delavenne X, Hart DP, Meunier S, Mismetti P. Individualized PK-based prophylaxis in severe haemophilia. Haemophilia 2018; 24 (Suppl. 02) 3-17
    PubMedGoogle Scholar
  • 28 McCarney R, Warner J, Iliffe S, van Haselen R, Griffin M, Fisher P. The Hawthorne Effect: a randomised, controlled trial. BMC Med Res Methodol 2007; 7 (01) 30
    CrossrefPubMedGoogle Scholar