Abstract
Objective: To investigate the pharmacokinetics and pharmacodynamics of the approved 900/1,200 mg dosing regimen for the terminal complement component 5 (C5) inhibitor eculizumab in patients with neuromyelitis optica spectrum disorder (NMOSD).Methods: Data were analyzed from 95 patients with aquaporin-4-IgG-positive NMOSD who received eculizumab during the PREVENT study (ClinicalTrials.gov: NCT01892345). Relationships were explored between eculizumab exposure and free complement C5 concentrations, terminal complement activity, and clinical outcomes.Results: Pharmacokinetic data were well-described by a two-compartment model with first-order elimination, and time-variant body-weight and plasmapheresis/plasma exchange effects. Steady-state serum eculizumab concentrations were achieved by Week 4 and were sustained, with serum trough eculizumab concentrations maintained above the 116 μg/ml threshold for complete complement inhibition throughout 168 weeks of treatment in all post-baseline samples from 89% of patients. Complete inhibition of terminal complement was achieved at Day 1 peak and pre-dosing trough eculizumab concentration in nearly all post-baseline samples assessed (free C5 <0.5 μg/ml in all post-baseline samples from 96% of patients; in vitro hemolysis <20% in all post-baseline samples from 93% of patients). Kaplan–Meier survival analysis of time to first relapse showed separation of eculizumab-treated patients from those receiving placebo, but no separation based on eculizumab exposure quartile, indicating an optimized dose regimen with maximized efficacy.Conclusions: The approved eculizumab dosing regimen (900/1,200 mg) for adults with aquaporin-4-IgG-positive NMOSD is confirmed by rigorous quantitative model-based analysis of exposure–response. The data demonstrate that eculizumab's mechanism of action translates into clinical effect by achieving rapid, complete, and sustained terminal complement inhibition.
Highlights
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder of the central nervous system (CNS), predominantly affecting the optic nerves and spinal cord, and characterized by severe and unpredictable attacks
The activation results in cleavage of complement protein C5 into C5a and C5b; increased concentrations of terminal complement components (C5a and sC5b-9) have been demonstrated in the cerebrospinal fluid (CSF) of patients with active NMOSD [12, 15]
Study Population and Study Design. This analysis was based on pharmacokinetic, pharmacodynamic, efficacy, and safety data from the randomized, double-blind, placebo-controlled, multicenter, Phase 3 PREVENT study (ClinicalTrials.gov: NCT01892345) of eculizumab in patients with AQP4-IgG-positive NMOSD
Summary
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder of the central nervous system (CNS), predominantly affecting the optic nerves and spinal cord, and characterized by severe and unpredictable attacks (relapses). These relapses can cause disabling neurologic damage, including weakness, numbness, bowel/bladder dysfunction, pain, paralysis, and blindness [1, 2]. The activation results in cleavage of complement protein C5 into C5a (which promotes inflammation) and C5b (which coordinates formation of the membrane attack complex); increased concentrations of terminal complement components (C5a and sC5b-9) have been demonstrated in the cerebrospinal fluid (CSF) of patients with active NMOSD [12, 15]. The complement activity rapidly causes damage to astrocytes, as well as permeabilization of the blood–brain barrier, leading to astrocyte necrosis, demyelination, and neuronal death [11, 16,17,18,19]
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