US head of Modeling and Simulation group Sanofi, United States
Objectives: Dupilumab, a fully human anti-interleukin (IL)-4Rα monoclonal antibody, inhibits signaling of IL-4 and IL-13, key drivers of type 2 inflammatory disease. Dupilumab has been approved for treatment of multiple type 2 diseases, including chronic obstructive pulmonary disease (COPD). The objectives of this analysis were to develop a population pharmacokinetics (PopPK) model characterizing dupilumab pharmacokinetics (PK) and to assess the influence of intrinsic and extrinsic factors on dupilumab PK in patients with COPD.
Methods: The analysis was conducted using pooled PK data at the dupilumab dose of 300 mg every 2 weeks, from two phase 3 trials (BOREAS [NCT03930732] and NOTUS [NCT04456673]) in adult patients with COPD and type 2 inflammation. A dupilumab global PopPK base model, including body weight effects, [1] was previously developed using pooled data from healthy subjects, patients with AD, and patients with asthma; we utilized this to characterize PK in patients with COPD. This global PopPK base model was used to fit the sparse PK data by estimating only key PK parameters (e.g. volume of central compartment, linear elimination rate constant, and nonlinear target-mediated rate of elimination with their respective interindividual variabilities), identified from sensitivity analysis. The remaining PK parameters were fixed with their initial estimated values from the global PopPK base model. The effect of selected covariates was evaluated using a stepwise forward addition and backward elimination, with an added emphasis on evaluating the effect of baseline disease characteristics. Standard diagnostic criteria were used to determine the appropriateness of the final PopPK model, including diagnostic plots, quality criteria, visual predictive checks, and bootstrapping.
Results: The final dataset included 923 patients with 6,369 dupilumab PK concentrations. The observed steady-state exposure was generally comparable across approved indications with type 2 diseases. The PK of dupilumab in patients with COPD was adequately described by a 2-compartment model with first-order absorption and parallel linear and nonlinear Michaelis–Menten elimination. Consistent with other indications, body weight was the primary source of variability in PK. Anti-drug antibody status, age, albumin, and study differences were identified as statistically significant covariates, but with limited or no clinically meaningful effect. All other covariates, including gender, race, creatinine clearance, and baseline biomarkers and disease characteristics, were not found to have statistically significant effects.
Conclusions: The PopPK model adequately described the PK of dupilumab in the COPD population. The PK of dupilumab in patients with COPD was generally consistent with that of other dupilumab indications.
Citations: [1] Zhang L, et al. Population pharmacokinetic meta-analysis of dupilumab in adult atopic dermatitis patients, asthma patients, and healthy subjects. 28th PAGE meeting, Jun 11–14, 2019. Available from: https://www.page-meeting.org/?abstract=9160.
