Base and Covariate Population Pharmacokinetic Analyses of Dupilumab Using Phase 3 Data

Abstract

Population pharmacokinetic base and covariate models were developed to study functional dupilumab for regulatory submissions, using data from healthy volunteers and patients with moderate-to-severe atopic dermatitis (AD) receiving intravenous or subcutaneous doses. Sixteen studies were pooled (N = 2115; 202 healthy volunteers, 1913 AD patients). The best model was a 2-compartment model with linear and Michaelis-Menten elimination and 3 transit compartments describing absorption. A stepwise approach to model building, with some parameters estimated using mostly rich data and subsequently fixed, was used to avoid adverse effects of sparse data and a steep target-mediated phase on pharmacokinetic parameters, which require rich sampling for proper estimation. Parameterization of models in terms of rates was a useful alternative to the parameterization in terms of clearances, allowing for a reduced number of covariates while providing accurate predictions. While antidrug antibodies, albumin, race, body mass index, and Eczema Area and Severity Index score were statistically significant covariates, only body weight had a notable effect on central volume, explaining interindividual variability. The model adequately described dupilumab pharmacokinetics in phase 3 trials.

Keywords: atopic dermatitis; dupilumab; monoclonal antibodies; phase 3; population pharmacokinetics; regulatory submissions.

Figure 1

Structural representation of model with parallel Michaelis‐Menten and linear elimination of dupilumab. F, bioavailability; IV, intravenous; k_cp, central‐to‐peripheral rate; k_pc, peripheral‐to‐central rate; k_a, absorption rate; k_e, elimination rate; K_m, Michaelis–Menten constant; SC, subcutaneous; V_c, central volume of distribution; V_m, maximum target‐mediated rate of elimination; V_p, peripheral volume.

Figure 2

Observed vs predicted dupilumab concentrations for primary covariate model (Model 4). Unit line and spline are provided in the figure. qw, weekly; q2w, every 2 weeks.

Figure 3

Visual predictive check of dupilumab concentrations by study and treatment regimen—primary covariate model (Model 4). PI, predicted interval; qw, weekly; q2w, every 2 weeks.

Figure 4

Plot of the dependence of clearance on serum dupilumab concentrations.

Figure 5

Median of simulated concentration of functional dupilumab over time by treatment. SC, subcutaneous; q1w, every week; q2w, every 2 weeks; q4w, every 4 weeks; q8w, every 8 weeks.