Although body weight affected pharmacokinetics, the investigators said dosing adjustments based on weight were not warranted.
A new report shows the pharmacokinetic properties of Dupixent (dupilumab) are similar in patients with asthma and atopic dermatitis (AD), and suggests body weight is the major factor affecting the drug’s variability among patients.
The findings, based on a pharmacokinetic model developed by investigators at Sanofi and Regeneron, were recently published in CPT: Pharmacometrics & Systems Pharmacology.
The authors explained that dupilumab is a recombinant human immunoglobulin-G4 monoclonal antibody that binds to the shared receptor component for interleukins 4 and 13, which are the key drivers of type 2 inflammation in asthma and similar diseases like AD. The FDA has approved dupilumab for teenagers and adults with eosinophilic phenotype or oral corticosteroid–dependent asthma. The drug is also approved in Europe for certain patients with severe asthma.
The investigators wanted to develop a model for dupilumab that would help them better understand which intrinsic and extrinsic factors might affect the pharmacokinetics of the therapy in patients with asthma. To do so, they followed the strategy of a previous model that looked at AD and developed their updated model by using 9 studies, from phase 1 to phase 3, that together included 202 healthy subjects and 1912 patients with asthma, of whom 68 were adolescents. The resulting PopPK model is believed to be the first such model examining dupilumab use in adolescents and adults with asthma.
“The model was a helpful tool to predict the impact of different dosing regimens or loading dose on the dupilumab [pharmacokinetic] profile and to optimize the study design for dosing regimen in other asthma studies,” the authors wrote.
The model showed no statistically significant difference between the pharmacokinetics of dupilumab in patients with asthma compared with healthy controls.
“Moreover, the disposition characteristics of dupilumab are comparable between asthma and AD populations, as the population parameter estimates, the observed/predicted exposures, as well as the main sources of variability observed in patients are consistent between the asthma and AD populations,” the investigators reported, concluding that disease status did not influence the drugs’ pharmacokinetics.
The authors looked at several other variables, including demographics and laboratory parameters, that might affect how the drug worked in patients, but found only body weight could explain the variability. For instance, the investigators found no apparent age effect between adolescents and adults, suggesting that the same dosing regimen is suitable for both age groups.
And although weight was found to impact the pharmacokinetics, the authors said weight-based dose adjustments were unnecessary.
“Even though body weight exerted a noticeable effect explaining between-subject variability in dupilumab [pharmacokinetics] in patients with asthma, given the magnitude of the effect on exposures and the limited difference in efficacy/safety across the weight categories, no dose adjustment is recommended with regard to body weight,” they said.
After developing their model, the investigators validated it using another study population of 103 oral corticosteroid–dependent patients with asthma. That analysis confirmed the efficacy of the developed model, which they said had “robust” predictive capabilities for such patients.
Zhang L, Gao Y, Li M, et al. Population pharmacokinetic analysis of dupilumab in adult and adolescent patients with asthma. CPT Pharmacometrics Syst Pharmacol. Published online July 27, 2021. doi:10.1002/psp4.12667