S.F. Koopman1, M.H. Cnossen2, R.A.A. Mathôt1
1Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Center, 2Department of Pediatric Hematology and Oncology, Erasmus MC Sophia Children’s Hospital, University Medical Center Rotterdam
Introduction: In haemophilia B patients on prophylaxis with an extended half-life factor IX (EHL-FIX) concentrate, pharmacokinetic (PK)-guided dosing can be applied to improve exposure (peak and trough FIX activity levels). It is known, however, that FIX activity in the plasma is not the only factor responsible for haemostasis as its extravascular presence also plays a role. Nonetheless, target FIX activity levels should be individually set according to bleeding tendency, presence of target joints and physical activity. To achieve this individualisation, both PK and pharmacodynamics (PD) should be taken into account. Our current objective was to examine the relationship between prophylactic dose, FIX activity levels and bleeding for rIX-FP (albutrepenonacog alfa, Idelvion®). Methods: Data from persons with haemophilia B requiring prophylaxis (FIX activity level =2 IU/dL) from five PROLONG-9FP clinical trials (CSL654_2001, CSL654_2004, CSL654_3001, CSL654_3002 and CSL654_3003) were combined. Individual PK profiles were constructed and the probability of bleeding was estimated with a parametric repeated time-to-event (RTTE) model. Bleeding was differentiated in damage-causing and nuisance bleeds. Nuisance bleeds were defined as bruising, mucosal bleeds and bleeds of an unknown cause. Damage-causing bleeds were defined as all bleeds that were not categorised as nuisance bleeds (submitted for publication). Simulations were performed on a virtual population of 1000 patients with a bodyweight of 70 kg and typical PK parameters resulting from the developed population PK model (submitted for publication) with weekly rIX-FP dosing targeting trough FIX activity levels of 1, 3, 5, 10 and 20 IU/dL in order to evaluate the relationship between trough FIX activity levels and annual bleeding hazard. Generally accepted trough FIX activity levels are currently =3 IU/dL to control breakthrough bleeding [1]. Analyses were performed separately to specifically evaluate damage-causing and nuisance bleeds. Results: Data included 2493 FIX activity levels and 514 bleeds from 114 unique patients with a median age of 26 years (range: 1–61) and median weight of 64 kg (range: 11–130). Patients were followed for a median of 416 days (range: 6–1233). Median weekly dose was 38.0 IU/kg (range: 6.5–71.4) and median FIX activity levels per patient was 15 (range: 2–60). In total, 238 (46%) joint, 268 (52%) trauma-related, 306 (60%) damage-causing and 208 (40%) nuisance bleeds occurred. In the RTTE analysis for all bleeds, an exponential hazard function best described the data resulting in an annual bleeding rate (ABR) of 7.3 year-1 without FIX activity in the plasma (SCALE). The probability of bleeding decreased with 50% (ABR = 3.7 year-1) at a FIX activity level (IC50) of 12 IU/dL. Variability in the bleeding hazard between persons with similar FIX activity levels was substantial (182%). At time of bleeding, the median FIX activity level was 21.4 IU/dL (range: 0.8 – 92). Successive bleeds were not found to be time-dependent, indicating that a bleed in itself does not influence the likelihood of a future bleed. In the RTTE analyses for damage-causing and nuisance bleeds specifically, a SCALE of 3.3 and 2.4 year-1, an IC50 of 12.2 and 12.3 IU/dL and a variability in the bleeding hazard of 275% and 175%, respectively, were found. Simulations suggest that a median patient presents with a median of 3 and 2 (trough FIX activity level of 1 IU/dL), 2 and 1 (trough FIX activity level of 3 IU/dL) to 0 (trough FIX activity level 20 IU/dL) for both damage-causing and nuisance bleeds, respectively, during one year. Conclusion: The observed PK-PD relationship demonstrates that the probability of bleeding at a specific FIX activity level varies considerably between patients. This underlines the importance of taking bleeding phenotype into account when individualising rIX-FP therapy which is also related to other physiological parameters. In addition, our simulations indicate that an ABR of 0 is achieved when trough FIX activity levels are maintained between 10-20 IU/dL, which are appreciably higher than generally accepted FIX activity levels to control breakthrough bleeding [1]. The presented RTTE model is able to quantify the individual relationship between bleeding and rIX-FP exposure in these trial patients supporting PK-PD guided dosing and is a basis for future physiologically-based PK models.
[1] Collins, P. W., Obaji, S. G., Roberts, H., Gorsani, D. & Rayment, R. Clinical phenotype of severe and moderate haemophilia: Who should receive prophylaxis and what is the target trough level? Haemophilia 27, 192–198 (2021).
Reference: PAGE 33 (2025) Abstr 11511 [www.page-meeting.org/?abstract=11511]
Poster: Clinical Applications