B. Wang(1), Z. Yao(1), L. Yan(1), W. White(2), H. Kawai(3), C. Ward(4), D. Raible(5), L. Roskos(2)
(1) Clinical Pharmacology & DMPK, MedImmune, Hayward, CA, USA;(2) Clinical Pharmacology & DMPK, MedImmune, Gaithersburg, MD, USA;(3) Clinical Science Department, Kyowa Hakko Kirin Co.,LTD., Tokyo, Japan;(4) Translational Sciences, MedImmune, Gaithersburg, MD, USA; (5) Clinical Development, MedImmune, Gaithersburg, MD, USA
Objectives: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of benralizumab, an afucosylated human IgG1 monoclonal antibody direct against interleukin-5 receptor, in healthy volunteers and asthma patients using a population approach.
Methods: Pharmacokinetic and blood eosinophil count data from two healthy volunteer studies (n=48, Japan) and four studies in asthma patients (n=141, North America) were pooled and simultaneously modeled in this meta-analysis. To reduce the parameter estimation bias the PHI subroutine implemented in NONMEM 7 was used to censor the zero observations. The final model was evaluated using posterior visual predictive check and bootstrapping.
Results: Benralizumab PK was adequately described by a two-compartment model with first-order elimination from the central compartment, and first-order absorption from the dosing site for subcutaneously administered benralizumab. The estimated systemic clearance and volume of distribution were typical for human IgG not subject to the target-mediated clearance (antigen-sink). Only body weight was identified as a relevant PK demographic covariate. The depletion of blood eosinophil counts was depicted by a modified transit model in which benralizumab induced destruction of eosinophils in each age compartment. A tissue compartment was also incorporated in the model to account for the extravascular eosinophils. Stochastic simulations demonstrated comparable PK exposure and eosinophil suppression in adolescence and adult subjects.
Conclusions: The mechanistic model appropriately described the PK of benralizumab and the depletion of blood eosinophil counts. Results from the meta-analysis facilitated the exposure-response relationship assessment and the selection of appropriate dose and dosing schedule for late-stage clinical studies.
Reference: PAGE 22 (2013) Abstr 2810 [www.page-meeting.org/?abstract=2810]
Poster: Other Drug/Disease Modelling