Fixed doses of N8‐GP prophylaxis maintain moderate‐to‐mild factor VIII levels in the majority of patients with severe hemophilia A. Issue 3 (11th June 2019)

• Record Type: Journal Article
• Authors: Chowdary, Pratima; Carcao, Manuel; Holme, Pål A.; Jiménez‐Yuste, Victor; Lentz, Steven R.; Møss, Judi; Poulsen, Lone H.; Shen, Chunduo; Tosetto, Alberto; Wheeler, Allison; Santagostino, Elena
• Is Part Of: Research and practice in thrombosis and haemostasis. Volume 3:Issue 3(2019)
• Page Start: 542
• Page End: 554
• Publication Date: 2019-06-11
• Subjects: factor VIII -- hemophilia A -- pharmacokinetics -- recombinant -- von Willebrand factor; Thrombosis -- Periodicals; Hemostasis -- Periodicals; 616.135005
• DOI: 10.1002/rth2.12220
• Languages: English
• ISSNs: 2475-0379

Abstract

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.