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...

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Vydané v:CPT: pharmacometrics and systems pharmacology Ročník 14; číslo 8; s. 1370 - 1380
Hlavní autori: Zhang, Li, Davis, John D., Kanamaluru, Vanaja, Xu, Christine
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States John Wiley & Sons, Inc 01.08.2025
John Wiley and Sons Inc
Wiley
Predmet:
Adolescent
Adult
Aged
Airway management
Anti-Asthmatic Agents - administration & dosage
Anti-Asthmatic Agents - pharmacokinetics
Anti-Asthmatic Agents - pharmacology
Antibodies, Monoclonal, Humanized - administration & dosage
Antibodies, Monoclonal, Humanized - pharmacokinetics
Antibodies, Monoclonal, Humanized - pharmacology
Asthma
Asthma - drug therapy
Asthma - physiopathology
Biomarkers
Bronchodilators
Dose-Response Relationship, Drug
Double-Blind Method
Drug dosages
dupilumab
Female
Forced Expiratory Volume - drug effects
forced expiratory volume in 1 s
Humans
Inflammation
Male
Middle Aged
Missing data
Models, Biological
Monoclonal antibodies
Patients
Pediatrics
Pharmacodynamics
Pharmacokinetics
Placebo effect
Population
population pharmacokinetic/pharmacodynamic
Severity of Illness Index
Software
Spirometry
Steroids
Young Adult
United States > US
asthma
forced expiratory volume in 1 s
population pharmacokinetic/pharmacodynamic
dupilumab
monoclonal antibodies
ISSN:2163-8306, 2163-8306
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Popis
Shrnutí: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 Emax 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.
Bibliografia:Li Zhang —Former employee (employed at Sanofi at the time of the study).
Funding
Research was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.
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Funding: Research was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.
ISSN:2163-8306
2163-8306
DOI:10.1002/psp4.70057