Pharmacometrician Teva Pharmaceuticals, Ltd., Israel
Disclosure(s):
Or Dotan, MA: No relevant disclosure to display
Objectives: TEV-53408 is a human monoclonal antibody (mAb) that binds to and neutralizes interleukin-15 currently being evaluated in celiac disease. Utilizing data collected during the Phase 1 first-in-human (FIH) study in healthy participants, this presented analysis sought to characterize pharmacokinetics (PK) of TEV-53408 and further anticipate the PK signature in patients for various indications.
Methods: Population PK modeling was used to describe the dynamics of the serum TEV-53408 concentrations over time, and several structural models were evaluated. A set of demographic and baseline characteristics were tested to explain the interindividual variability in selected PK parameters (i.e., covariate analysis).
During model development, population PK models were assessed using the evaluation of individual and population mean parameter estimates and their precision as measured by the percent standard error of the population mean estimate relative to known priors or physiological values, and by graphical examination of standard diagnostic and population analysis goodness-of-fit plots.
Various steps of analysis dataset preparation, exploratory analysis and simulations were performed in R and appropriate R packages. Nonlinear-mixed effect modeling was performed using NONMEM.
Results: A two-compartment model with first-order absorption, linear and saturable elimination, body weight at baseline as a covariate on clearance, maximum apparent clearance rate and peripheral volume, and fixed inter-individual variability of the Michaelis-Menton constant, best described the serum TEV-53408 concentration-time data. The model was then used in simulation mode to anticipate outcomes with alternative doses and dosing regimens in a virtual participant population.
Conclusions: The resulting population PK model adequately characterizes PK following subcutaneous administration of TEV-53408. This provides a robust quantitative platform for future decision making and informing dose selection for subsequent clinical trials.
