Suhaila O. Suliman (1), Himanshu Naik (2), Majd Mouded (2), Chris Stebbins (2), Guolin Zhao (2), Guochen Song (2), Shelia Violette (2), Diana Gallagher (2), Kubra Kamisoglu (2), Million Arefayene(2)
(1) University of Iowa, USA, (2) Biogen, USA
Introduction:
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease caused by progressive scarring in the lungs tissue [1]. To date, there is no known curative therapy for IPF patients [2]. BG00011 is first-in-class humanized IgG1 monoclonal antibody that blocks αvβ6 integrin, which is highly upregulated in IPF patients and responsible for activation of latent transforming growth factor-beta (TGF-β), a key regulator of IPF. BG00011 is currently being investigated in phase 2B clinical trial.
Objectives:
Understand impact of pre-defined predictors on BG00011 exposure and characterize relationship between BG11 exposure and PD modulation (ratio of phosphorylated-SMAD to total-SMAD proteins (pSMAD/tSMAD).
Methods:
The BG00011 serum concentration obtained from a single ascending dose healthy volunteer study and serum concentration and PD (the ratio of phosphorylated-SMAD to total-SMAD proteins (pSMAD/tSMAD)) obtained from a multiple ascending dose in IPF patients were used in development of PK and PK/PD model. One and two compartment models with linear and non-linear clearance were evaluated as base PK models. The AUC at steady state (AUCss) over the dosing interval after the last dose and the pSMAD/tSMAD percentage change from the baseline was used for development of PK/PD model using a naïve pool approach. The following steps were followed to achieve the objective: (1) exploratory PK data analyses were performed graphically, (2) base PK model structure was developed, (3) effect of body weight, gender and disease status were evaluated on PK parameters (4) PK/PD model for BG00011 was developed using the predicted exposure (AUCss) based upon the final PK model. PK and PK/PD models were developed sequentially using Monolix (Version 2018R1) and Phoenix (version 7.0), respectively. Parameter estimates with associated standard errors, diagnostic plots and visual predictive checks were used for model evaluation.
Results:
In total, 794 serum concentrations and 19 pSMAD/tSMAD ratio data from patients were included in the population analysis. The two-compartment model with first order absorption and combination of linear and nonlinear elimination model was identified as optimal with all parameters estimated with high precision [PK: CL (0.034), Vc (2.31), Vp (6.07), Vmax (26.8), Km (389); RSE% for all parameters < 25%]. The covariate analysis indicated that body weight, gender and disease status had no effect on PK parameters. The predictive ability of the model demonstrated that the median, 10th, and 90th percentiles of predictions well-captured the observed data in the evaluated dose range.
The relationship between BG00011 concentration and pSMAD/tSMAD ratio was best described by a direct response model with sigmoidal effect on pSMAD/tSMAD ratio mediated by BG00011 concentrations. The model-estimated Imax was 129.2 hr·mg/mL.
Conclusion:
The population PK/PD model adequately characterized BG00011 PK/PD in IPF patients. The nonspecific disposition component estimates (CL, Vss) were consistent with results obtained for other IgG1 monoclonal antibodies [3]. Covariates on PK parameters are not expected to have any clinical impact at the proposed Phase 2B dose. The PK/PD model will be updated and used to support future dose and regimen selection.
References:
[1] Ley, B. and H.R. Collard. Epidemiology of idiopathic pulmonary fibrosis. Clin Epidemiol, 2013. 5: 483-92.
[2] Vega-Olivo, M. and G.J. Criner. Idiopathic pulmonary fibrosis: A guide for nurse practitioners. Nurse Pract, 2018. 43(5): 48-54.
[3] Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinetic, 2010 Oct;49(10): 633-59.
Reference: PAGE 28 (2019) Abstr 8852 [www.page-meeting.org/?abstract=8852]
Poster: Drug/Disease Modelling - Other Topics