Page 132 - 2021_07-Haematologica-web

Ferrata Storti Foundation
Haematologica 2021 Volume 106(7):1902-1909
Hemostasis
Factor VIII activity and bleeding risk during prophylaxis for severe hemophilia A:
a population pharmacokinetic model
Andreas Tiede,1 Faraizah Abdul Karim,2 Victor Jiménez-Yuste,3
Robert Klamroth,4 Sandra Lejniece,5 Takashi Suzuki,6 Andreas Groth7 and Elena Santagostino8
1Hannover Medical School (MHH), Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany; 2Haemophilia Centre, National Blood Centre, Kuala Lumpur, Malaysia; 3Hospital Universitario La Paz, Autónoma University, Madrid, Spain; 4Haemophiliezentrum, Klinik für Innere Medizin, Vivantes Klinikum im Friedrichshain, Berlin, Germany; 5Rîga East Clinical University Hospital, Chemotherapy and Hematology Clinic, Rîga, Latvia; 6Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan; 7Novo Nordisk A/S, Søborg, Denmark and 8Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Cà Granda Foundation, Maggiore Hospital Policlinic, Milan, Italy
ABSTRACT
During factor VIII prophylaxis for severe hemophilia A, bleeding risk increases with time when factor VIII activity is below 1%. However, maintaining trough activity above 1% does not protect all patients from bleeding. The relationship between factor VIII activity during prophylaxis and bleeding risk has not been thoroughly studied. We investi- gated factor VIII activity and annualized bleeding rate for spontaneous bleeds during prophylaxis. A population pharmacokinetic model derived from three clinical trials was combined with dosing data and information on bleeding from patients’ diaries. Each patient’s time on prophylaxis was divided into five categories of predicted activity (0-1%, >1-5%, >5-15%, >15-50%, and >50%). Exposure time, mean factor VIII activity, and number of bleeds (from the patients’ diaries) were calculated for each activity cate- gory, and annualized bleeding rates estimated using negative binomial regression and a parametric model. Relationships between these bleeding rates and factor VIII activity were evaluated by trial phase (pivotal vs. exten- sion) and age (adults/adolescents [≥12 years] vs. children [0-<12 years]). In total (n=187 patients; 815 patient-years’ exposure), factor VIII activity was predicted to be >1% for 85.64% of the time. The annualized bleeding rate decreased as factor VIII activity increased in each trial phase and age group. However, for a given activity level, bleeding rate differed substantially by trial phase and age. This suggests that bleeding risk can change over time and is influenced by factors independent of factor VIII pharmacokinetics and trough levels. When making decisions regarding target trough levels and the prophylactic regimen, the patients’ age, joint disease activity, and other bleeding risk determinants should be taken into consideration. Clinical trial registration numbers: NCT00840086; NCT01138501; NCT00984126
Introduction
Hemophilia is classified according to factor VIII (FVIII) plasma activity as “severe” (<1% of normal activity), “moderate” (1-5%), or “mild” (>5%-<40%).1,2 Severe hemophilia is characterized by spontaneous, recurrent bleeds into joints and muscles which can lead to chronic arthropathy, muscular atrophy, and defor- mities. Converting the clinical phenotype of hemophilia from severe to moderate has been the rationale for prophylaxis.3 In patients with severe hemophilia A, pro- phylaxis with replacement FVIII can prevent bleeds and structural joint damage when initiated at a young age,4 and can decrease bleeding frequency, slow joint dis- ease progression, and improve quality of life - even when initiated in adults with established joint damage.5
Correspondence:
ANDREAS TIEDE
tiede.andreas@mh-hannover.de
Received: November 27, 2019. Accepted: April 22, 2020. Pre-published: April 23, 2020.
https://doi.org/10.3324/haematol.2019.241554
©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
1902
haematologica | 2021; 106(7)
ARTICLE