Population Pharmacokinetic Modeling Of On-Demand And Surgical Use Of Nonacog Beta Pegol (N9-GP) And rFIXFc Based Upon The paradigm 7 Comparative Pharmacokinetic Study
Received 29 May 2019
Accepted for publication 9 September 2019
Published 13 November 2019 Volume 2019:10 Pages 391—398
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Dr Martin H Bluth
Mindy L Simpson,1 Roshni Kulkarni,2 Carmen Escuriola Ettingshausen,3 Rikke Medom Meldgaard,4 David L Cooper,5 Robert Klamroth6
1Pediatric Hematology/Oncology, Rush University Medical Center, Chicago, IL, USA; 2Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA; 3HZRM – Haemophilia Centre Rhein-Main, Frankfurt-Mörfelden, Mörfelden-Walldorf, Germany; 4Novo Nordisk A/S, Søborg, Denmark; 5Novo Nordisk Inc, Plainsboro, NJ, USA; 6Department for Internal Medicine, Vascular Medicine and Haemostaseology, Vivantes Klinikum, Berlin, Germany
Correspondence: Mindy L Simpson
Pediatric Hematology/Oncology, Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612, USA
Tel +1 312 563 3995
Aim/objective: Understanding pharmacokinetic (PK) differences between standard and extended half-life (EHL) products is important, particularly for factor IX (FIX), where differences are more significant than for factor VIII. Two single-dose PK trials showed N9-GP achieves higher FIX levels and greater area-under-the-curve than pdFIX, rFIX, and rFIXFc through higher recovery and longer terminal half-life. In paradigm 7, N9-GP demonstrated consistently favorable PK characteristics compared with rFIXFc. Collins et al explored population PK differences between N9-GP and pdFIX/rFIX based upon paradigm 1 data. This analysis uses population PK models based upon the paradigm 7 trial.
Methods: 15 patients (21–65 years) with hemophilia B received single 50-IU/kg doses of N9-GP and rFIXFc ≥21 days apart. A population PK model developed from single-dose PK profiles simulated plasma FIX activity following dosing for surgery and on-demand treatment of bleeds. Simulations explored doses and frequencies required to sustain target World Federation of Hemophilia (WFH) factor activity levels.
Results: PK profiles of N9-GP and rFIXFc were described by one- and three-compartment models, respectively. Simulations predicted significantly reduced dosing frequency and consumption for N9-GP than rFIXFc. For severe bleeds, a single N9-GP dose (80 IU/kg) is sufficient to maintain WFH-recommended FIX levels, whereas multiple rFIXFc doses are required. For surgery, redosing in the first week with N9-GP is modeled at day 6 vs rFIXFc dosing at 6, 30, 54, 78, and 126 hrs. For life-threatening bleeds, N9-GP is required at days 0, 3, 6, 13, and 18 vs rFIXFc redosing after 6 hrs with 10 additional doses at 24-, 48-, and 72 hr intervals.
Conclusion: PK modeling approaches based upon direct comparative studies offer insights into PK differences between EHL FIX products. Model simulations show N9-GP may allow on-demand treatment and perioperative management with 55–75% fewer injections and 65–74% lower overall factor concentrate consumption than rFIXFc.
Keywords: N9-GP, rFIXFc, population PK modeling, paradigm 7 trial
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]