Analysis of peginterferon β-1a exposure and Gd-enhanced lesion or T2 lesion response in relapsing-remitting multiple sclerosis patients.
The effect of subcutaneous (SC) peginterferon β-1a exposure on reduction of gadolinium-enhanced (Gd+) lesion count over time was evaluated in patients with relapsing-remitting multiple sclerosis (RRMS) in a Phase 3 study (ADVANCE). Patients were randomized to receive SC injections of placebo (n = 500), 125 mcg every-2-weeks (n = 512), or 125 mcg every-4-weeks (n = 500) for 1 year, and then active treatment in the second year. Steady state 4-week AUC (AUCss) was derived for each individual based on sparse pharmacokinetic (PK) sample and a population PK model. Several longitudinal count models, including marginal, mixed effect, and mixture models, were compared to explore the relationship between AUCss and Gd+ lesion count (or T2 lesion count). A mixture model which divided subjects into two subpopulations by low and high baseline lesion activity was found to yield best goodness-of-fit for the data. In this model, the point estimate and 95 % CI for drug effect slope on log(λ) are -0.0256 (-0.0304, -0.0216) for Gd+ lesion and -0.0147 (-0.0170, -0.0124) for T2 lesion. This suggested that reduction of Gd+ lesion (or T2 lesion) count over time is significantly related to SC peginterferon β-1a exposure, and that the increased reduction lesion count with the every-2-week regimen versus the every-4-week regimen was driven by the higher exposure achieved in that treatment arm (mean Gd+ lesion count 0.2 and 0.7 at Year 2, respectively). The every-2-week regimen produced an exposure range that was close to the plateau range of the exposure-response curve, supporting its selection as the regulatory approved dosage.
Biogen, Cambridge, MA, USA. yaming.hang@biogen.com.
Yaming
Y
Hang
Biogen, Cambridge, MA, USA.
Xiao
X
Hu
Biogen, Cambridge, MA, USA.
Jie
J
Zhang
Biogen, Cambridge, MA, USA.
Shifang
S
Liu
Biogen, Cambridge, MA, USA.
Aaron
A
Deykin
Biogen, Cambridge, MA, USA.
Ivan
I
Nestorov
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D003287:Contrast Media / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005682:Gadolinium / Q000008:administration & dosage; D006207:Half-Life; D006801:Humans; D007089:Image Enhancement; D007279:Injections, Subcutaneous; D016899:Interferon-beta / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008954:Models, Biological; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012008:Recurrence; D016896:Treatment Outcome
D000276:Adjuvants, Immunologic; D003287:Contrast Media; D011092:Polyethylene Glycols; D016899:Interferon-beta; D005682:Gadolinium; C428112:peginterferon beta-1a
Exposure–response; Longitudinal count data; Mixture model; Multiple sclerosis; Peginterferon β-1a; Population pharmacokinetics