Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX

被引:57
作者
Collins, P. W. [1 ]
Moss, J. [2 ]
Knobe, K. [3 ]
Groth, A. [4 ]
Colberg, T. [5 ]
Watson, E. [6 ,7 ]
机构
[1] Cardiff Univ, Sch Med, Arthur Bloom Haemophilia Ctr, Cardiff CF14 4XW, S Glam, Wales
[2] Novo Nordisk AS, Clin Pharmacol Biopharm, Soborg, Denmark
[3] Lund Univ, Ctr Thrombosis & Haemostasis, Malmo, Sweden
[4] Novo Nordisk AS, Quantitat Clin Pharmacol, Soborg, Denmark
[5] Novo Nordisk AS, Haemophilia, Med & Sci, Soborg, Denmark
[6] Novo Nordisk AS, DMPK, Malov, Denmark
[7] Novo Nordisk AS, Bioanal, Malov, Denmark
关键词
hemophilia B; nonacog beta pegol; pharmacokinetic modeling; prophylaxis; recombinant factor IX; SEVERE HEMOPHILIA-A; PROPHYLACTIC TREATMENT; FACTOR-VIII; SAFETY; AGE; CONCENTRATE; EXPERIENCE; CHILDREN; EFFICACY; PROTEIN;
D O I
10.1111/jth.12000
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) molecule with a prolonged half-life. Objectives: To provide information on potential dose regimens for N9-GP for phase 3 pivotal and surgery trials. Methods: A population pharmacokinetic model was developed from single-dose data derived from the first human-dose trial with N9-GP in hemophilia B patients, and was used to extrapolate to steady-state conditions for different N9-GP dose regimens for prophylaxis. The model was also used to compare prophylaxis using N9-GP with standard prophylactic regimens using rFIX or plasma-derived (pd) FIX (40 IU kg(-1) every third day). Plasma activity following dosing with N9-GP, rFIX and pdFIX for surgery and on-demand treatment of bleeds was also simulated. Results: A linear two-compartmental model best described the pharmacokinetic profiles of N9-GP, rFIX and pdFIX. A prophylactic regimen of 10 U kg(-1) N9-GP once weekly predicted mean peak and trough levels of 18 and 4.2 U dL(-1), while 40 U kg(-1) once weekly predicted values of 72 and 17 U dL(-1), respectively. Standard prophylactic regimens with rFIX and pdFIX predicted mean peak and trough levels of 34 and 3.9 IU dL(-1) for rFIX, and mean values of 43 and 2.1 IU dL(-1) for pdFIX. Additional simulations predicted significantly reduced dosing frequency and factor concentrate consumption for N9-GP vs. rFIX and pdFIX for surgery and the treatment of bleeds. Conclusions: N9-GP may allow prophylaxis, surgical dosing regimens and on-demand treatment of bleeding episodes with less frequent injections and lower factor concentrate consumption; this possibility is being investigated in prospective clinical trials.
引用
收藏
页码:2305 / 2312
页数:8
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