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Base and Covariate Population Pharmacokinetic Analyses of Dupilumab Using Phase 3 Data
Author(s) -
Kovalenko Pavel,
Davis John D.,
Li Meng,
Rippley Ronda,
Ardeleanu Marius,
Shumel Brad,
Graham Neil M.H.,
Pirozzi Gianluca,
Kamal Mohamed A.,
DiCioccio A. Thomas
Publication year - 2020
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.780
Subject(s) - covariate , medicine , pharmacokinetics , population , dupilumab , body mass index , atopic dermatitis , logistic regression , pharmacology , statistics , immunology , mathematics , environmental health
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.