Fixed doses of N8-GP prophylaxis maintain moderate-to-mild factor VIII levels in the majority of patients with severe hemophilia A

Pratima Chowdary, Manuel Carcao, Pål A Holme, Victor Jiménez-Yuste, Steven R Lentz, Judi Møss, Lone H Poulsen, Chunduo Shen, Alberto Tosetto, Allison Wheeler, Elena Santagostino

Research output: Contribution to journalArticle

Abstract

Background: N8-GP is an extended half-life recombinant factor VIII developed for prophylaxis and treatment of bleeds in patients with hemophilia A.

Objective: To assess pharmacokinetic (PK) characteristics of N8-GP in previously treated patients with severe hemophilia A, model the time spent at hemophilia thresholds of ≥1 and ≤5 IU/dL (moderate) or >5 IU/dL (mild) FVIII levels during N8-GP prophylaxis, and investigate the relationship between N8-GP half-life and von Willebrand factor (vWF).

Methods: PK assessments were obtained from patients with severe hemophilia A (FVIII < 1 IU/dL) participating in 4 clinical trials: pathfinder 1 (20-60 years); pathfinder 2 (12-17 and ≥18 years); pathfinder 5 (0-11 years), and pathfinder 7 (25-71 years). All PK profiles were assessed after washout and considered single-dose PK profiles. Pre- and postdose FVIII activity at steady state was measured at all visits.

Results: From 69 patients, 108 PK profiles of N8-GP 50 IU/kg were assessed. Adults/adolescents received 50 IU/kg every 4 days, achieving mean trough levels of 3.0 IU/dL (95% confidence interval, 2.6-3.5, adults) and 2.7 IU/dL (1.8-4.0, adolescents). Children received 60 IU/kg twice weekly, leading to mean trough levels of 1.2 IU/dL (0.8-1.6, 0- to 5-year-olds) and 2.0 IU/dL (1.5-2.7, 6- to 11-year-olds). PK modeling predicted children dosed every 3 days and adults/adolescents dosed every 3 to 4 days would maintain FVIII levels >5 and >1 IU/dL for >80% and 100% of the time, respectively. N8-GP half-life correlated linearly with von Willebrand factor levels in adults/adolescents, less in children.

Conclusions: Prophylaxis with fixed intervals (Q4D/twice weekly) and fixed weight-based dosing (50/60 IU/kg) ensured >1 IU/dL FVIII trough levels in both adults and children.

Original languageEnglish
Pages (from-to)542-554
Number of pages13
JournalResearch and practice in thrombosis and haemostasis
Volume3
Issue number3
DOIs
Publication statusPublished - Jul 2019

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    Chowdary, P., Carcao, M., Holme, P. A., Jiménez-Yuste, V., Lentz, S. R., Møss, J., Poulsen, L. H., Shen, C., Tosetto, A., Wheeler, A., & Santagostino, E. (2019). Fixed doses of N8-GP prophylaxis maintain moderate-to-mild factor VIII levels in the majority of patients with severe hemophilia A. Research and practice in thrombosis and haemostasis, 3(3), 542-554. https://doi.org/10.1002/rth2.12220