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

Abstract

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, GermanyCorrespondence: Mindy L SimpsonPediatric Hematology/Oncology, Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612, USATel [phone]Email [email protected]/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

Keywords

• n9-gp
• rfixfc
• population pk modeling
• paradigm 7 trial