The Posology of Dupilumab in Pediatric Patients With Atopic Dermatitis

Abstract

Dupilumab demonstrated efficacy with an acceptable safety profile in two randomized, double-blind, placebo-controlled, parallel-group, phase III trials in adolescents (12-17 years; LIBERTY AD ADOL) and children (6-11 years; LIBERTY AD PEDS) with atopic dermatitis (AD) treated for 16 weeks. Here, we present the pharmacokinetic profiles and exposure-response (E-R) relationships of dupilumab that guided the posology in these populations. A total of 251 adolescent patients with moderate-to-severe AD were randomized to subcutaneous dupilumab monotherapy every 2 weeks (q2w; 200 mg q2w, baseline weight < 60 kg; 300 mg q2w, ≥ 60 kg), dupilumab 300 mg every 4 weeks (q4w; non-weight tiered), or placebo; 367 children with severe AD were randomized to dupilumab q2w (100 mg q2w, baseline weight < 30 kg; 200 mg q2w, ≥ 30 kg), dupilumab 300 mg q4w, or placebo. Children received concomitant topical corticosteroids in addition to dupilumab, and loading doses were administered at the start of therapy. Mean dupilumab trough concentrations at week 16 for weight subcategories in each dosing regimen were compared with adult exposures for the approved dupilumab 300 mg q2w regimen. Positive E-R relationships were demonstrated between dupilumab trough concentrations and AD outcome measures across patient populations and regimens; no relationship was observed with treatment-emergent conjunctivitis. Based on these analyses, a weight-tiered posology was proposed for adolescents (200/300 mg q2w in patients 30-< 60 kg/≥ 60 kg) and children (300 mg q4w in patients 15-< 30 kg, 200 mg q2w in patients 30-< 60 kg) with moderate-to-severe AD.

Trial registration: ClinicalTrials.gov NCT03054428 NCT03345914.

Figure 1

Mean (±SD) concentration‐time course of dupilumab by treatment‐weight group in (a) adolescents aged 12–17 and (b) children aged 6–11 years (PKAS). *US Food and Drug Administration approved doses. BLQs were set to 0. Nominal time points until week 16 were used for analysis. BLQ, below limit of quantification; PK, pharmacokinetics; PKAS, PK analysis set; q2w, every 2 weeks; q4w, every 4 weeks.

Figure 2

Concentrations of functional dupilumab in serum at week 16 by body weight group and dose group in adults, adolescents aged 12–17 years, and children aged 6–11 years. Mean values: adults 300 mg q2w, 74.6 mg/L; adolescents 200 mg q2w < 60 kg, 51.3 mg/L; 300 mg q2w ≥ 60 kg, 57.9 mg/L; 300 mg q4w < 60 kg, 27.2 mg/L; 300 mg q4w ≥ 60 kg, 12.7 mg/L; children 100 mg q2w < 30 kg, 62.6 mg/L; 200 mg q2w ≥ 30 kg, 86.0 mg/L; 300 mg q4w < 30 kg, 98.7 mg/L; 300 mg q4w ≥ 30 kg, 53.9 mg/L. All dose regimens were compared to adults. *US Food and Drug Administration approved doses. Diamonds signify mean values; vertical lines extending from top to bottom are the maximum value below upper fence and minimum value above lower fence, respectively; circles are outliers defined by the “1.5 rule”, namely, when less than (Q1 – 1.5*IQR) or greater than (Q3 + 1.5*IQR), with IQR = Q3–Q1. Outliers above a concentration of 165 mg/L were removed from analysis to enable data visualization and comparison of dose regimens. BLQs were set to 0. Adults are patients in studies R668‐AD‐1334 and R668‐AD‐1416; adolescents are patients in study R668‐AD‐1526; and children (6–11 years) are patients in study R668‐AD‐1652. BLQ, below limit of quantification; IQR, interquartile range; 2qw, every 2 weeks; q4w, every 4 weeks.

Figure 3

Exposure‐efficacy relationships. (a) Probability of response (proportions of patients with) for IGA 0 or 1 by week 16 dupilumab concentrations. (b) Probability of response (proportions of patients with) for EASI‐75 by week 16 concentrations. (c) Percentage change in EASI from baseline to week 16 vs. trough concentration (CRAS). (d) Percentage change in Peak Pruritus Numerical Rating Scale (NRS) from baseline to week 16 vs. C_trough (CRAS). *US Food and Drug Administration approved doses. Outliers above concentrations of 165 mg/L were removed from analysis. BLQs were set to 0. BLQ, below limit of quantification; CRAS, concentration‐response analysis set; C_trough, trough concentration; EASI, Eczema Area and Severity Index; EASI‐75, ≥ 75% reduction from baseline in EASI; PK, pharmacokinetics; PKAS, PK analysis set; q2w, every 2 weeks; q4w, every 4 weeks. (a, b) Blue line = mean regression line, gray area = confidence area around regression line. (c, d) Blue line = locally estimated scatterplot smoothing (LOESS), gray area = 95% confidence interval.

Figure 4

Logistic regression analysis between events of conjunctivitis and concentration of dupilumab. *US Food and Drug Administration approved doses. Outliers above concentrations of 165 mg/L were removed from analysis. BLQs were set to 0. Blue line = mean regression line, gray area = confidence area around regression line. BLQ, below limit of quantification; C_trough, trough concentration; q2w, every 2 weeks; q4w, every 4 weeks.