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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Factor VIII
Hemophilia A
Half-Life
von Willebrand Factor
Pharmacokinetics
Weights and Measures
Therapeutics

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

In: Research and practice in thrombosis and haemostasis, Vol. 3, No. 3, 07.2019, p. 542-554.

Research output: Contribution to journalArticle

Chowdary, P, Carcao, M, Holme, PA, Jiménez-Yuste, V, Lentz, SR, Møss, J, Poulsen, LH, 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, vol. 3, no. 3, pp. 542-554. https://doi.org/10.1002/rth2.12220
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. / Fixed doses of N8-GP prophylaxis maintain moderate-to-mild factor VIII levels in the majority of patients with severe hemophilia A. In: Research and practice in thrombosis and haemostasis. 2019 ; Vol. 3, No. 3. pp. 542-554.
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title = "Fixed doses of N8-GP prophylaxis maintain moderate-to-mild factor VIII levels in the majority of patients with severe hemophilia A",
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.",
author = "Pratima Chowdary and Manuel Carcao and Holme, {P{\aa}l A} and Victor Jim{\'e}nez-Yuste and Lentz, {Steven R} and Judi M{\o}ss and Poulsen, {Lone H} and Chunduo Shen and Alberto Tosetto and Allison Wheeler and Elena Santagostino",
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T1 - Fixed doses of N8-GP prophylaxis maintain moderate-to-mild factor VIII levels in the majority of patients with severe hemophilia A

AU - Chowdary, Pratima

AU - Carcao, Manuel

AU - Holme, Pål A

AU - Jiménez-Yuste, Victor

AU - Lentz, Steven R

AU - Møss, Judi

AU - Poulsen, Lone H

AU - Shen, Chunduo

AU - Tosetto, Alberto

AU - Wheeler, Allison

AU - Santagostino, Elena

PY - 2019/7

Y1 - 2019/7

N2 - 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.

AB - 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.

U2 - 10.1002/rth2.12220

DO - 10.1002/rth2.12220

M3 - Article

C2 - 31294338

VL - 3

SP - 542

EP - 554

JO - Research and practice in thrombosis and haemostasis

JF - Research and practice in thrombosis and haemostasis

SN - 2475-0379

IS - 3

ER -