Eculizumab Pharmacokinetics and Pharmacodynamics in Patients With Neuromyelitis Optica Spectrum Disorder

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.

Keywords: autoimmune; complement; eculizumab; exposure-response analysis; neuromyelitis optica spectrum disorder; pharmacodynamics; pharmacokinetics.

Conflict of interest statement

PS and XG were employees of Alexion Pharmaceuticals, Inc. at the time the work described in this paper was undertaken; RP is an employee of Alexion Pharmaceuticals, Inc.; HJK and FB are employees of Certara Strategic Consulting, which received funding from Alexion Pharmaceuticals. The authors declare that this study received funding from Alexion Pharmaceuticals Inc. The funder had the following involvement with the study as sponsor: study design; collection, analysis, interpretation of data, the writing of this article, and the decision to submit it for publication. Editorial assistance was provided by Piper Medical Communications, funded by Alexion Pharmaceuticals Inc.

Copyright © 2021 Singh, Gao, Kleijn, Bellanti and Pelto.

Figures

Figure 1

Serum eculizumab concentrations during the study. Mean (95% confidence interval) trough and peak serum eculizumab concentrations in patients who received eculizumab in the PREVENT study; eculizumab concentrations below the lower limit of quantification (9.38 μg/ml) were analyzed as 4.69 μg/ml (half the lower limit of quantification). Eculizumab concentrations above 116 μg/ml (dashed line) indicate sufficient concentration to achieve complete complement inhibition.

Figure 2

Estimated body weight-normalized eculizumab exposure parameters for the total patient population, Asian, non-Asian, Japanese, and non-Japanese patients. Results are shown for parameters at steady state: (A) AUC, (B) Cmax, and (C) Ctrough. Exposures were normalized by body weight using the exponent estimated in the final model. AUC, area under the concentration–time curve within one dosing interval; Cmax, peak concentration; Ctrough, concentration at the end of the dosage interval; ss, steady state.

Figure 3

Serum free C5 concentrations and complement-mediated hemolytic activity in serum during the study. (A) Mean (95% CI) serum free C5 concentrations. Free C5 concentrations below the lower limit of quantification (0.0274 μg/ml) were analyzed as 0.0137 μg/ml (half the lower limit of quantification). Free C5 concentrations below 0.5 μg/ml (dashed line) indicate complete terminal complement inhibition. No free C5 data were available for one patient. (B) Mean (95% CI) percent in vitro complement-mediated hemolytic activity of serum samples. Hemolysis values above 20% (dashed line) indicate incomplete inhibition of hemolysis. No hemolysis data were available for one patient. For both analyses, samples were taken before and after eculizumab infusion (i.e., at eculizumab serum trough and peak concentrations, respectively); samples taken before and after infusion in patients receiving placebo are shown for comparison. C5, complement protein 5; CI, confidence interval. aSamples taken 5–90 min before infusion. bSamples taken 60 min after the completion of infusion. Data are plotted for timepoints when samples were available for ≥ 10 patients. The numbers reported below the graphs are the numbers of patients for whom samples were tested at that timepoint.

Figure 4

Eculizumab exposure–response profiles for serum free C5 concentration and hemolytic activity. Scatterplots of (A) time-matched serum free C5 concentrations and eculizumab concentrations, and (B) time-matched percent hemolysis and eculizumab concentrations. Vertical lines at eculizumab 116 μg/ml and horizontal lines at free C5 0.5 μg/ml in panel A and 20% hemolysis in panel B show thresholds representing complete terminal complement inhibition for serum eculizumab concentration, and for free C5 concentration and hemolytic activity, respectively. C5, complement component 5.

Figure 5

Kaplan–Meier survival plots for time to first adjudicated on-trial relapse, according to eculizumab exposure. Relapse-free survival curves for each exposure quartile for time to first adjudicated on-trial relapse in eculizumab-treated patients. For comparison, the survival curve is also shown for patients receiving placebo. AUCss is based on the maintenance dose of 1,200 mg eculizumab. One eculizumab-treated patient for whom no post-hoc pharmacokinetic parameters were obtained was excluded from the analysis. AUCss, area under the concentration–time curve within one dosing interval at steady state; Q1, 1st quartile; Q2, 2nd quartile; Q3, 3rd quartile; Q4, 4th quartile.