Impact of Adopting Population Pharmacokinetics for Tailoring Prophylaxis in Haemophilia A Patients: A Historically Controlled Observational StudyFunding 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.
26 September 2018
09 December 2018
27 January 2019 (eFirst)
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.
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.
- 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
- 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
- 3 Iorio A. Using pharmacokinetics to individualize hemophilia therapy. Hematology (Am Soc Hematol Educ Program) 2017; 2017 (01) 595-604
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 11 Hilliard P, Funk S, Zourikian N. , et al. Hemophilia Joint Health Score reliability study. Haemophilia 2006; 12 (05) 518-525
- 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
- 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
- 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
- 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
- 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
- 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
- 18 Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1 (8476): 307-310
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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