(W-026) Population pharmacokinetic and pharmacodynamic analysis of natural killer cell levels in response to TEV-53408, an anti-interleukin 15 monoclonal antibody, in healthy volunteers
Pharmacometrician Teva Pharmaceuticals, Ltd., Israel
Disclosure(s):
Or Dotan, MA: No relevant disclosure to display
Objectives: TEV-53408 is a human monoclonal antibody that binds to and neutralizes interleukin-15 (IL-15), which is involved in T cell and natural killer (NK) cell homeostasis and immune-mediated diseases. TEV-53408 is currently being evaluated in celiac disease. The objectives of this analysis were to characterize the pharmacodynamic (PD) effect on NK cell counts, based on the data collected during a Phase 1, first-in-human (FIH) study in 114 healthy participants, and further predict the PK/PD signature in patients for various indications.
Methods: A population PK/PD model was used to describe the dynamics of NK cell counts in relation to 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 the model development, population PK/PD 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: The serum concentration of TEV-53408 over time was best described by a two-compartment PK model with first-order absorption, linear and saturable apparent elimination, and body weight at baseline as a covariate on apparent clearance, maximum apparent clearance rate and apparent peripheral volume. The relationship between TEV-53408 exposures and NK cell count was best described by a PD model with proliferating and transport compartments1 that included a Michaelis-Menten equation for prediction of the NK cell counts, with treatment type (e.g., placebo or not) and the baseline level of NK cells as covariates on baseline circulation of NK cells (i.e., the level of NK cells in each PD compartment). 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/PD model provides a robust quantitative platform for future decision making and informing dose selection for subsequent clinical trials.
Citations: [1] Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 2002; 20(24): 4713-4721. doi:10.1200/JCO.2002.02.140
