(W-127) Population pharmacokinetic and pharmacodynamic modeling of free serum interleukin-15 in response to TEV-53408, an anti-interleukin 15 monoclonal antibody, in healthy volunteers.

Dongwoo Kang, n.a. – Associate Director, Pharmacometrics, Quantitative Clinical Pharmacology & Biosimilars, Teva Branded Pharmaceutical Products R&D, Inc., West Chester, PA, USA; Or Dotan, n.a. – Manager, Department of Quantitative Clinical Pharmacology & Biosimilars, Teva Pharmaceutical Industries Ltd., Netanya, Israel; Andrijana Radivojevic, n.a. – Consultant, intiGROWTH LLC, Miami, FL, USA; Victoria Schnir, n.a. – Senior manager, Department of Quantitative Clinical Pharmacology & Biosimilars, Teva Pharmaceutical Industries Ltd., Netanya, Israel; Dikla Gutman, n.a. – Director, Department of Quantitative Clinical Pharmacology & Biosimilars, Teva Pharmaceutical Industries Ltd., Netanya, Israel; Rajendra Singh, n.a. – Senior Director, Pharmacometrics, Quantitative Clinical Pharmacology & Biosimilars, Teva Branded Pharmaceutical Products R&D, Inc., West Chester, PA, USA

Objectives: TEV-53408 is a human monoclonal antibody that binds to and neutralizes interleukin 15 (IL-15) currently being evaluated in celiac disease. The objective of this presented analysis was to develop a population pharmacokinetics/pharmacodynamics (PK/PD) model to describe the time course of free serum IL-15 following both single and multiple TEV-53408 subcutaneous (SC) doses in healthy participants.

Methods: Data from 115 participants across 8 dose levels including placebo from the Phase 1 first-in-human study was used for model development and validation. A sequential approach was used for model development where population PK model was first developed to describe the TEV-53408 PK concentration-time profiles. The post-hoc individual PK exposures were then used as TEV-53408 drug concentrations to develop a PK/PD model for free serum IL-15 levels. Different PK/PD structural models were tested. The nonlinear-mixed effect modeling software NONMEM (version 7.5) was used for model development, and RStudio software (version 3.5.2) was used for exploratory analysis.

Results: The final population PK/PD model consisted of a two compartment PK model with first-order absorption and linear and saturable apparent elimination to describe the TEV-53408 drug ligand profile; and a one compartment target-mediated drug disposition PD model incorporating delayed feedback to the free serum IL-15 compartment to describe the delayed increase beyond baseline¹. The final model adequately described the free serum IL-15 levels post-dose reduction and subsequent increase beyond baseline at different dose levels. The time to increase beyond baseline of free serum IL-15 was also found to be dose dependent.

Conclusions: A population PK/PD model was developed to describe the reduction and subsequent increase beyond baseline of free serum IL-15 following SC dose of TEV-53408. This model allowed for simulation of free serum IL-15 under different dosing scenarios and served as a guiding piece in dose selection of subsequent TEV-53408 clinical trials.

Citations: 1. Aston PJ, Derks G, Agoram BJ, & van der Graaf PH. A mathematical analysis of rebound in a target-mediated drug disposition model: II. With feedback. J. Math. Biol. (2017) 75:33-84.