Population Pharmacokinetic Modeling of Inebilizumab in Subjects with Neuromyelitis Optica Spectrum Disorders, Systemic Sclerosis, or Relapsing Multiple Sclerosis.
Journal
Clinical pharmacokinetics
ISSN: 1179-1926
Titre abrégé: Clin Pharmacokinet
Pays: Switzerland
ID NLM: 7606849
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
accepted:
23
08
2021
pubmed:
1
11
2021
medline:
26
4
2022
entrez:
31
10
2021
Statut:
ppublish
Résumé
Inebilizumab is a humanized, affinity-optimized, afucosylated immunoglobulin (Ig)-G1κ monoclonal antibody that binds to CD19, resulting in effective depletion of peripheral B cells. It is being developed to treat various autoimmune diseases, including neuromyelitis optica spectrum disorders (NMOSD), systemic sclerosis (SSc), and relapsing multiple sclerosis (MS). Pharmacokinetic data from a pivotal study in adult subjects with NMOSD and two early-stage studies in subjects with SSc or relapsing MS were pooled and simultaneously analyzed using a population approach. Upon intravenous administration, the pharmacokinetics of inebilizumab were adequately described by a two-compartment model with parallel first-order and time-dependent nonlinear elimination pathways. An asymptotic nonlinear elimination suggests that inebilizumab undergoes receptor (CD19)-mediated clearance. The estimated systemic clearance (CL) of the first-order elimination pathway (0.188 L/day) and the volume of distribution (V The presence of antidrug antibodies, status of hepatic or renal function, and use of small-molecule drugs commonly used by subjects with NMOSD had no clinically relevant impact on the pharmacokinetics of inebilizumab. The nonlinear elimination pathway at the 300 mg therapeutic dose level is not considered clinically relevant.
Sections du résumé
BACKGROUND AND OBJECTIVE
Inebilizumab is a humanized, affinity-optimized, afucosylated immunoglobulin (Ig)-G1κ monoclonal antibody that binds to CD19, resulting in effective depletion of peripheral B cells. It is being developed to treat various autoimmune diseases, including neuromyelitis optica spectrum disorders (NMOSD), systemic sclerosis (SSc), and relapsing multiple sclerosis (MS).
METHODS
Pharmacokinetic data from a pivotal study in adult subjects with NMOSD and two early-stage studies in subjects with SSc or relapsing MS were pooled and simultaneously analyzed using a population approach.
RESULTS
Upon intravenous administration, the pharmacokinetics of inebilizumab were adequately described by a two-compartment model with parallel first-order and time-dependent nonlinear elimination pathways. An asymptotic nonlinear elimination suggests that inebilizumab undergoes receptor (CD19)-mediated clearance. The estimated systemic clearance (CL) of the first-order elimination pathway (0.188 L/day) and the volume of distribution (V
CONCLUSIONS
The presence of antidrug antibodies, status of hepatic or renal function, and use of small-molecule drugs commonly used by subjects with NMOSD had no clinically relevant impact on the pharmacokinetics of inebilizumab. The nonlinear elimination pathway at the 300 mg therapeutic dose level is not considered clinically relevant.
Identifiants
pubmed: 34718986
doi: 10.1007/s40262-021-01071-5
pii: 10.1007/s40262-021-01071-5
pmc: PMC8891208
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Aquaporin 4
0
inebilizumab
74T7185BMM
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
387-400Informations de copyright
© 2021. The Author(s).
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