Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab

Abstract

Objective: Mepolizumab is a humanized IgG1 monoclonal antibody that blocks human IL-5 from binding to the IL-5 receptor, which is mainly expressed on eosinophils. Eosinophils are key cells in the inflammatory cascade of various diseases, including asthma. This study investigated the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between exposure of mepolizumab subcutaneous (SC) administration and blood eosinophil reduction compared with intravenous (IV) administration in adult subjects with asthma.

Methods: In this multi-center, randomized, open-label, parallel-group, repeat-dose study, 70 adult subjects received one of four possible treatment regimens: mepolizumab 12.5, 125, or 250 mg SC or 75 mg IV. In addition to analyzing the dose and PK/PD relationship, absolute bioavailability, safety, tolerability, and incidence of anti-mepolizumab antibodies were evaluated.

Results: Blood eosinophil levels decreased in a dose-dependent manner with the lowest (12.5 mg) dose clearly differentiating from the other doses. A non-linear inhibition Imax model based on blood eosinophil levels at week 12 identified that the SC doses providing 50% and 90% of maximal blood eosinophil inhibition were 11 mg (95% confidence interval (CI): 5.19 - 16.85) and 99 mg (95% CI: 47 - 152), respectively. The route of administration did not affect the exposure-response relationship. The estimated mepolizumab SC absolute bioavailability (arm) was 74% (90% CI: 54 - 102%). The safety profile of mepolizumab was favorable.

Conclusions: A dose-dependent reduction in blood eosinophils across all mepolizumab doses investigated was observed. The subcutaneous absolute bioavailability was 74%. The route of administration did not affect the mepolizumab exposure eosinophil response relationship.

Figure 1.. Subject disposition.

Figure 2.. Individual mepolizumab model-predicted and observed plasma concentration-time profiles with population prediction.

Figure 3.. Individual model-predicted and observed blood eosinophils-time profiles with population prediction.

Figure 4.. Proportional change from baseline in blood eosinophil data (Geometric mean ± standard error). Blue arrows indicate mepolizumab administration. N’s represent number of patients within each treatment group with available data at each time point. The order from the top is Mepolizumab SC 12.5 mg, Mepolizumab IV 75 mg, Mepolizumab SC 125 mg, Mepolizumab SC 250 mg. A proportional change from baseline of < 1 represents a reduction in eosinophil levels. A proportional change from baseline of 1 represents no change in eosinophil levels. Prior to log-transformation, zero values were imputed with half the minimum value across all dose groups and time points.

Figure 5.. Proportion of baseline blood eosinophils remaining at week 12 (day 84) (model predictions and 95% CIs) non-linear Imax dose-response model). 10^R = 10^{β(Bl) + (D × Imax)/(D + ID50).} R = Change from baseline in log₁₀-transformed blood eosinophil levels (week 12); D = Dose (mg) (SC or SC dose equivalent); Bl = Baseline log₁₀ blood eosinophils (mean across all dose groups = –0.36); β = baseline covariate regression coefficient (estimate: –0.84; 95% CI: (–1.14 – –0.55)); Imax = Maximum reduction in log₁₀ blood eosinophils (week 12) (estimate: –1.27; 95% CI: (–1.43 to –1.11)); ID₅₀ = Dose inducing half maximal drug effect (estimate: 11.02; 95% CI: (5.19 – 16.85)); 75 mg IV assumed to equate to 100 mg SC within model. Prior to log₁₀-transformation, zero values were imputed with half the minimum value across all dose groups and time points.

Figure 6.. Proportional change from baseline in sputum eosinophil data (%) (Geometric mean ± standard error). Blue arrows indicate mepolizumab administration. N’s represent number of patients within each treatment group with available data at each timepoint. The order from the top is Mepolizumab SC 12.5 mg, Mepolizumab IV 75 mg, Mepolizumab SC 125 mg, Mepolizumab SC 250 mg. A proportional change from baseline of < 1 represents a reduction in eosinophil levels. A proportional change from baseline of 1 represents no change in eosinophil levels.

Figure 7.. Serum IL-5 (total) data (log10 scale) (mean ± standard error). Blue arrows indicate mepolizumab administration. N’s represent number of patients within each treatment group with available data at each time point. The order from the top is Mepolizumab SC 12.5 mg, Mepolizumab IV 75 mg, Mepolizumab SC 125 mg, Mepolizumab SC 250 mg; Results below the limit of quantification have been imputed with half the lower limit of quantification.

Figure S1.. Study design schematic.

Equation.. Equation