(W-090) Physiologically Based Pharmacokinetic Model of Vedolizumab in Adult Patients with Inflammatory Bowel Disease

Ryota Tanaka, NA – Visiting Researcher, Division of Translational and Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center.; Kei Irie, NA – Research Associate, Division of Translational and Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center.; Tomoyuki Mizuno, NA – Associate Professor, Division of Translational and Clinical Pharmacology and Department of Pediatrics, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, College of Medicine

Objective: Vedolizumab (VDZ) is an anti-α4β7-integrin antibody used to treat Ulcerative colitis (UC) and Crohn's disease (CD) in pediatric and adult patients. However, the impact of physiological changes in children and young adults on the VDZ pharmacokinetic (PK) has not been well-characterized due to limited PK data. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict VDZ PK in adult patients with UC and CD, establishing a basis for constructing a pediatric PBPK model.

Method: The unique PK behavior of the antibody, characterized by convective disposition via lymph, binding to FcRn to escape endosomal degradation, and target-mediated drug disposition (TMDD), was modeled using the Simcyp Simulator (version 22). Most drug-related parameters were derived from either Simcyp default parameters for endogenous IgG or were obtained from the literature. The receptor (target) degradation rate constant (Kdeg), the rate of VDZ uptake into endothelial space (Kup), and additional linear clearance were estimated using PK data from healthy volunteers. After qualifying the model with healthy volunteer data, the target abundance (Rmax) and equilibrium dissociation constant (KD) were adjusted based on sensitivity analysis to capture the PK profiles of VDZ in patient populations. VDZ concentration-time profiles after intravenous (IV) infusion were simulated using a virtual population (n=100), and PK parameters were estimated to evaluate the predictive performance.

Results: For healthy volunteer populations ^[1], the geometric mean of predicted/observed ratios (P/O ratios) of the area under the concentration-time curve from zero to infinity (AUC0-∞), peak concentration (Cmax), and clearance (CL) were within a ±1.25-fold difference across various VDZ doses from 0.2 to 10mg/kg. After adjusting the Rmax and KD, the geometric mean of the P/O ratio of Cmax and AUC for specific time-periods across VDZ doses from 2.0 to 10mg/kg also fell within a ±1.25-fold difference in adult patients with mild to moderate active UC ^[2]. Additionally, the P/O mean ratio of the trough serum concentration levels of moderate to severe UC and CD adult patients at the induction and maintenance phases remained within a 2-fold difference ^[3,4].

Conclusion: An adult PBPK model for VDZ was successfully developed and qualified using data from healthy volunteers and patients with UC and CD. This model provides a foundation for constructing a pediatric model, which will explore the impact of pediatric physiology on VDZ disposition to facilitate precision dosing of VDZ therapy in pediatric patients.

Citations: [1] Rosario, et al. Clinical Drug Investigation (2016), 36(11), 913–923.
[2] Parikh, et al. Inflammatory Bowel Diseases (2012),18(8), 1470–1479.
[3] Feagan, et al. New England Journal of Medicine (2013), 369(8), 699–710.
[4] Sandborn, et al. New England Journal of Medicine (2013), 369(8), 711–721.