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Pharmacokinetic and Clinical Improvements after PK-guided Switch from Standard Half-life to Extended Half-life Factor VIII Products

1Hospital Universitari i Politecnic La Fe, Pharmacy Department and Haemostasis and Thrombosis Unit, Valencia, Spain, 2Hospital Universitari i Politecnic La Fe, Haemostasis and Thrombosis Unit, Valencia, Spain, 3Vall d'Hebron University Hospital, Haemostasis and Thrombosis Unit, Barcelona, Spain, 4Sant Joan de Déu Children's Hospital, Pediatric Hematology, Barcelona, Spain, 5Hospital Regional Universitario de Málaga, Haemostasis and Thrombosis Unit, Málaga, Spain, 6Hospital Álvaro Cunqueiro, Haemostasis and Thrombosis Unit, Vigo, Spain, 7Hospital Universitari Son Espases, Haemostasis and Thrombosis Unit, Mallorca, Spain, 8Hospital de la Santa Creu i Sant Pau, Haemostasis and Thrombosis Unit, Barcelona, Spain, 9Hospital Universitario Miguel Servet, Haemostasis and Thrombosis Unit, Zaragoza, Spain, 10Hospital Universitari Son Espases, Pharmacy Department, Mallorca, Spain, 11Hospital Universitario Miguel Servet, Pharmacy Department, Zaragoza, Spain, 12Hospital Universitari i Politecnic La Fe, Pharmacy Department, Valencia, Spain

Abstract Number: PB1035

Meeting: ISTH 2020 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical

Background: Extended half-life (EHL) factor VIII (FVIII) requires improvements in half-life (t1/2) and area under the curve (AUC) of 1.3 and 1.25 times compared to standard half-life (SHL) products.

Aims: The aim of this study is compare pharmacokinetics (PK) after the switch from SHL to EHL in hemophilia A (HA) patients.

Methods: Multicenter comparative, cross-sectional, prospective study analyzing PK differences after switch from SHL to EHL (efmoroctocog-alfa [rFVIII-Fc] and rurioctocog-alfa pegol [PEG-rFVIII]). WAPPS-Hemo® was used to analyze PK parameters: t1/2; AUC, peak level, trough level at 24, 48, 72 h and time to reach FVIII levels of 1, 2, 5%. Ratio of t1/2and AUC, nº weekly doses, dose/kg/week, annual bleeding rate (ABR) and annual joint bleeding rate (AJBR) before/after the switch were compared. Wilcoxon and Kruskal-Wallis tests (SPSS®) were employed.

Results: Eighty-seven patients from 8 Spanish hospitals were analyzed (62 rFVIII-Fc; 25 PEG-rFVIII), 83 had severe HA and 4 moderate HA, with a median age of 30 years (range=3-64).
All PK parameters were improved, ABR and AJBR were reduced, as well as dose/kg/week (16.9%, IQR:8.7-32.8%) and weekly infusion frequency (30%, IQR:0-33.3%) (Tables 1-2). In 14 younger patients the dose/kg/week was increased a median of 28.6% (IQR:11.7-40-7%). The median ratios of t1/2 and AUC were 1.4 (IQR:1.3-1.6) and 1.7 (IQR:1.3-2.2) in the entire cohort. In patients with ≥12 years treated with EHL ratios of t1/2 and AUC were 1.4 (IQR:1.3-1.7) and 1.8 (IQR:1.3-2.3), and in patients < 12 years treated with rFVIII-Fc were 1.3 (IQR:0.9-1.5) and 1.4 (IQR:1.1-2.1). No differences were observed in PK parameters in patients aged ≥12 years treated with rFVIII-Fc vs. PEG-rFVIII (Tables 1-2).

Conclusions: EHL FVIII have shown significant PK improvements, reductions in ABR and AJBR, avoiding one weekly infusion number and dose/kg/week. Outside the clinical trial setting, we have observed an increase in t1/2 and AUC ratios accordingly to EHL definition.

PK parameters SHL: median (IQR) EHL: median (IQR) P-value rFVIII-Fc (n=46): median (IQR) PEG-rFVIII (n=25): median (IQR) P-value
t1/2 (h) 12.5 (9.5-15.8) 18.3 (13.3-23.5) <0.001 20.3 (15.0-23.8) 19.8 (14.8-23.8) 0.736
AUC ((IU*h)/L) 9166 (7082-12349) 15805 (12184-21930) <0.001 16456 (12682-21930) 17811 (13072-25327) 0.613
Peak level (IU/dL) 70.5 (56.8-81.0) 80.0 (68.0-97.5) <0.001 76.0 (63.0-95.0) 94.0 (72.0-99.0) 0.099
Trough level at 24h 13.1 (9.2-18.8) 24.6 (19.9-34.6) <0.001 26.7 (20.7-34.6) 31.7 (22.7-39.9) 0.295
Trough level at 48h 3.9 (2.0-7.1) 9.9 (5.9-17.4) <0.001 10.8 (8.1-17.9) 14.9 (6.7-19.6) 0.576
Trough level at 72h 1.5 (0.9-3.0) 4.1 (2.1-8.5) <0.001 5.0 (2.9-8.5) 7.0 (2.3-9.4) 0.880
T5% 43.3 (33.0-58.8) 66.0 (51.5-91.0) <0.001 71.9 (59.0-91.5) 83.0 (52.6-93.9) 0.970
T2% 63.4 (48.5-80.3) 93.0 (72.3-126.0) <0.001 103.4 (82.0-127.4) 112.8 (74.9-129.8) 0.802
T1% 84.0 (67.9-109.8) 122.5 (92.6-160.3) <0.001 136.5 (106.0-163.1) 143.8 (96.8-166.6) 0.634

[Table 1. Comparisons between PK parameters after the switch between SHL to EHL FVIII (entire cohort) and between EHLs (patients aged ≥12 years).]

Clinical variables SHL: median (IQR) EHL: median (IQR) P-value rFVIII-Fc (N=46): median (IQR) PEG-rFVIII (N=25): median (IQR) P-value
Age (years) Not evaluated Not evaluated Not evaluated 33.5 (19.0-46.0) 37.0 (30.0-42.0) 0.665
Weigh (kg) 70 (55-84) 70 (57-87) 0.055 72 (64-90) 82 (72-94) 0.132
Nº weekly doses 3.0 (2.0-3.0) 2.0 (1.8-2.3) <0.001 2.0 (1.8-2.3) 2.0 (2.0-2.3) 0.831
Dose (IU/kg/week) 74.5 (58.0-105.2) 65.7 (44.8-96.5) <0.001 60.5 (43.0-87.0) 51.7 (44.7-67.4) 0.191
ABR (N=47) 2.0 (0.0-5.0) 0.0 (0.0-2.0) 0.001 1.0 (0.0-3.5) 0.0 (0.0-0.0) 0.148
AJBR (N=26) 1.0 (0.0-4.0) 0.0 (0.0-1.0) 0.007 1.0 (0.0-1.0) 0.0 (0.0-0.0) 0.373

[Table 2. Comparisons between clinical variables after the switch between SHL to EHL FVIII (entire cohort) and between EHLs (patients aged ≥12 years).]

To cite this abstract in AMA style:

Megías-Vericat JE, Bonanad S, Martínez García MF, Berrueco R, Mingot-Castellano EM, Rodríguez López M, Canaro Hirnyk M, Mateo Arranz J, Calvo Villas JM, Haya S, Benitez O, Mesegué Medea M, Albo López C, Palomero-Massanet A, Vilalta Seto N, Larrodé Leciñena I, Cid AR, Poveda JL. Pharmacokinetic and Clinical Improvements after PK-guided Switch from Standard Half-life to Extended Half-life Factor VIII Products [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/pharmacokinetic-and-clinical-improvements-after-pk-guided-switch-from-standard-half-life-to-extended-half-life-factor-viii-products/. Accessed September 27, 2023.

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