Semi-Mechanistic Population Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling of Dupilumab on Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) in Uncontrolled Moderate-To-Severe Asthma.

Abstract

In this study, we investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship of dupilumab as an add-on therapy in the intent-to-treat (ITT) uncontrolled moderate-to-severe asthma population and identified the factors significantly contributing to variability in forced expiratory volume in 1 second; (FEV₁). A semi-mechanistic population PK/PD model was developed using data from two placebo-controlled pivotal studies in 2654 adult and adolescent patients (n = 794 treated with placebo; n = 1860 treated with dupilumab 200 mg [400-mg loading dose] or 300 mg [600-mg loading dose] administered subcutaneously every 2 [Q2W] or 4 weeks [Q4W]). Treatment effect was described using a dupilumab concentration-dependent direct-response E_max model, and placebo effect was described using an empirical time-dependent function. Demographic variables, baseline disease characteristics, type-2 inflammation biomarkers, and immunogenicity were tested as covariates using the stepwise forward selection and backward elimination method. Baseline type-2 inflammation biomarkers (fractional exhaled nitric oxide [FeNO] level and blood eosinophil [EOS] count) were found to be significant covariates for FEV₁, with greater efficacy in patients with elevated biomarker levels. None of the other tested covariates, including age (12-87 years), had a significant impact on FEV₁. The PK/PD model predicted near-maximum FEV₁ response (0.1 L) over a dose of dupilumab. 200-300 mg Q2W in patients with moderate-to-severe asthma.