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- Arvanitakis, Alexandros, et al.
(author)
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A comparison of MyPKFiT and WAPPS-Hemo as dosing tools for optimizing prophylaxis in patients with severe haemophilia A treated with Octocog alfa
- 2021
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In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 27:3, s. 417-424
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Journal article (peer-reviewed)abstract
- Introduction: MyPKFiT and the Web-Accessible Population Pharmacokinetic service—Hemophilia (WAPPS-Hemo) are web-based population-based applications developed for helping physicians individualize and optimize replacement therapy. Although MyPKFiT is intended for Octocog alfa and Rurioctocog alfa pegol use only, the WAPPS-Hemo is applicable to all factor VIII concentrates. Aim: To compare MyPKFiT and WAPPS-Hemo as dosing tools for optimizing treatment of patients with severe haemophilia A on regular prophylaxis with Octocog alfa in a real-world setting. Methods: Fourteen patients with severe haemophilia A (median age 30.8 years; range 20–71) were enrolled. The FVIII activity was measured twice after a regular dose of Octocog alfa by the chromogenic and the one-stage assays. PK analyses were performed using each tool and dosing estimations to reach trough levels of 1%, 3% or 5% after 48 h. Findings were calculated and compared. Results: The two PK algorithms yielded similar t½ independent of the type of FVIII assay used. However, there were significant differences in the time to reach 1%, 3% and 5%. The WAPPS-Hemo generated 10–12 h longer time to a trough of 1% and up to 4 h for the troughs of 3% and 5%. Accordingly, the doses estimated by WAPPS-Hemo for a daily regimen were between 28% and 100% of those proposed by MyPKFiT. Conclusions: MyPKFiT and WAPPS-Hemo provided similar half-life estimations for Octocog alfa independent of the FVIII assay used. The doses suggested by WAPPS-Hemo to reach specific troughs were overall lower, which may have implications for treatment optimization.
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| 2. |
- Arvanitakis, Alexandros, et al.
(author)
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Clinical outcome and adherence rate in Scandinavian patients with intermediate-intensity prophylaxis before and after the switch of standard half-life FVIII products to BAY 81–8973
- 2022
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In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 28:2, s. 223-229
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Journal article (peer-reviewed)abstract
- Introduction: Treatment optimization in haemophilia A can be achieved by choice of FVIII product and knowledge of pharmacokinetics (PK), phenotype and adherence. A favourable PK profile of BAY 81–8973 (octocog alfa) (Kovaltry, Bayer AB) compared to other standard half-life (SHL) FVIII products has been suggested. Aim: To evaluate whether the switch to BAY 81–8973, using the same dosing schedule, impact factor consumption and bleed rates, taking arthropathy and adherence into account. Methods: Forty patients on prophylaxis with SHL (median age 40.5 years) attending the haemophilia treatment centres in Malmö and Oslo were enrolled. The annualised bleeding rate (ABR) and joint bleeding rate (AJBR) before and after the switch to BAY 81–8973 was calculated. PK analyses were performed with WAPPS-Hemo. Joint health status and treatment adherence were assessed. Results: The median ABR and AJBR was 0 before and after the switch, at both centres. The median yearly factor consumption was 3,345 IU/Kg/year in the entire study group corresponding to intermediate-intensity prophylaxis in most patients and with significantly more used in Malmö (3,862 IU/Kg/year), compared to Oslo (2,337 IU/Kg/year) (P.006). There was no correlation between arthropathy and bleeding. The median BAY 81–8973 t½ was 20 h (range 7.5–29 h), with significant correlation to VWF levels, and 13.4 h after exclusion of VWF outliers. Adherence to treatment was 97%. Conclusions: Concentrate switch, using mainly intermediate-intensity regimens with high adherence rates, preserves excellent prophylaxis outcome using standard half-life FVIII products, indicating the value of individualized prophylaxis and close follow-up.
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| 3. |
- Arvanitakis, Alexandros
(author)
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Haemophilia A - In pursuit of optimised outcomes via personalised treatment
- 2024
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Doctoral thesis (other academic/artistic)abstract
- Haemophilia A (HA) is a hereditary bleeding disorder, characterised by deficiency of coagulation factor VIII (FVIII). Repeated joint bleeds can lead to permanent joint damage. FVIII replacement therapy has a high cost and can reduce but not completely prevent bleeding. This thesis aims to promote personalised treatment and optimised outcomes through a clinical and pharmacokinetic characterisation. Paper I compared the PK estimations by two population-PK tools, MyPKFiT and WAPPS-Hemo, in a cohort of male patients with severe HA treated with octocog alfa. Both web tools were able to overcome assay discrepancy and produced similar FVIII half-life estimations. However, WAPPS-Hemo generated significantly longer estimations of time to various FVIII trough levels, and as a result, significantly lower dosing proposals than MyPKFiT, with possible clinical implications. Paper II investigated a cohort of patients with severe and moderate HA in Malmö and Oslo, after the switch from standard half-life (SHL) FVIII products to BAY 81-8973. The median annualised bleeding rate was 0 before and after the switch, despite the presence of arthropathy and mostly intermediate intensity dose regimens. Treatment adherence was excellent. The Oslo centre had significantly lower annual FVIII consumption. We concluded that personalised prophylaxis and good adherence can reduce FVIII consumption and maintain haemostatic efficacy. Paper III investigated the underlying reasons for the difference in FVIII consumption between the Malmö and Oslo cohorts in Paper II. This analysis showed that most patients in Oslo were on secondary prophylaxis with intermediate dose intensity, whereas most patients in Malmö were on primary prophylaxis. Secondary prophylaxis prevents bleeds but at a cost of more arthropathy and reduced health-related quality of life, compared to higher intensity primary prophylaxis. Additionally, non-null F8 genotypes may allow lower factor consumption with similar haemophilia joint health score (HJHS) and bleeding rates, compared to null genotypes. In Paper IV, the long-term joint outcomes, bleeding phenotype, and prophylaxis implementation in childhood were examined in patients born after 1980, with severe HA on primary prophylaxis. This study showed that primary prophylaxis is effective in delaying but does not completely prevent the gradual development of arthropathy in severe HA, with total HJHS rising to a median of 4 at 35-40 years. We concluded that joint assessments should begin at an early age and prophylaxis escalation should proceed expeditiously to prevent bleeds.
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| 4. |
- Arvanitakis, Alexandros, et al.
(author)
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Impact of timing of prophylaxis commencement, F8 genotype and age on factor consumption and health-related quality of life in patients with severe haemophilia A
- 2023
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In: Haemophilia. - 1351-8216. ; 29:4, s. 1032-1038
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Journal article (peer-reviewed)abstract
- Introduction: The timing of prophylaxis and F8 genotype can impact treatment outcomes in adults with severe haemophilia A (HA). Aim: To investigate how F8 genotype, timing, and type of prophylaxis influence arthropathy, bleeding rates, factor consumption and health-related quality of life (HRQoL). Methods: Thirty-eight patients with severe HA were enrolled. Bleeding events were recorded retrospectively during median 12.5 months. F8 gene variants were classified as null or non-null. Joint health and HRQoL were assessed with HJHS and EQ-5D-5L, respectively. Results: The median age at prophylaxis start was 1.25 years in the primary prophylaxis group (N = 15, median age 26 years) and 31.5 years in the secondary group (N = 22, 45 years), respectively. There were significant differences in the medians of HJHS (4 vs. 20, p <.001), EQ-5D-5L index (0.9647 vs. 0.904, p =.022), EQ VAS (87 vs. 75, p =.01) and FVIII consumption (3883 vs. 2737 IU/kg/year, p =.02), between the primary and secondary groups, respectively. Median annualized bleeding rate (ABR) was 0 for both groups. Twenty-five null and thirteen non-null F8 gene variants were identified. In the secondary prophylaxis group, lower median FVIII consumption (1926 vs. 3370 IU/kg/year) was shown for non-null compared to null variants, respectively, with similar ABR and HJHS. Conclusion: Delayed prophylaxis start with intermediate dose intensity prevents bleeds but at a cost of more arthropathy and reduced HRQoL, compared to higher intensity primary prophylaxis. Non-null F8 genotype may allow lower factor consumption with similar HJHS and bleeding rates, compared to null genotype.
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| 5. |
- Arvanitakis, Alexandros, et al.
(author)
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Primary prophylaxis implementation and long-term joint outcomes in Swedish haemophilia A patients
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In: Haemophilia. - 1351-8216.
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Journal article (peer-reviewed)abstract
- Introduction: Primary prophylaxis is the gold standard in severe haemophilia A (SHA) but time to escalate the prophylaxis regimen varies. Aim: Assess prophylaxis implementation and long-term joint health outcomes in SHA with primary prophylaxis. Methods: Adult male patients born after 1980, with SHA on primary prophylaxis, started before the age of 3 years and second joint bleed, and no history of FVIII inhibitors, were enrolled. Repeated joint-health examinations were performed with HJHS or HEAD-US; VERITAS-PRO assessed adherence. Results: Thirty patients were enrolled with, at inclusion, median age 33.5 years, annualized bleed rate and joint bleed rate 0, and FVIII consumption 4232 IU/kg/year, respectively. The median age was 1.2 years, at prophylaxis start once weekly with a median FVIII dose of 47.7 IU/kg, and 1.7 years, by the time escalation to a final regimen had occurred, with a median infusion frequency of thrice weekly and FVIII dose 41.7 IU/kg, respectively. Older age correlated with later transition to escalated prophylaxis (p <.001). Longer time to escalated prophylaxis correlated to more bleeds (p <.001). Median HJHS increased slowly, reaching 4 at 35–40 years. HJHS at 15–20 years correlated with higher HJHS afterwards. Median total HEAD-US score was 1 and correlated with HJHS (p <.001). Median VERITAS-PRO score was 36, indicating good treatment adherence. Conclusion: Primary prophylaxis is effective but does not completely prevent the gradual development of arthropathy in SHA. Joint assessments with HJHS should start at an early age, as they correlate with arthropathy in later life. Prophylaxis escalation should proceed expeditiously to prevent bleeds.
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