Figure 1.

QSP model workflow. A virtual patient is represented as an appropriately parameterized model describing the neutrophil life cycle. This model can be solved to generate simulations of neutrophil counts in blood under homeostatic or avadomide-perturbed conditions. Avadomide effect is determined by the sequential evaluation of PK, PD, and PD-driven alteration of the neutrophil maturation. Model simulations iterated for a large cohort of virtual patients allow capturing the global pattern of neutropenia in the disease cohort under investigation. Finally, simulation results are postprocessed to compute toxicity endpoints of interest. The neutrophil life cycle model is based on a compartmental structure. The proliferation pool represents committed proliferative neutrophil precursors. From a model idealization standpoint, these cells have specific characteristics: they can proliferate but not self-renew and can proceed to subsequent maturation stages, represented in the model as a sequence of transit compartments. These compartments (i.e., transit 1, transit 2, and transit 3) do not have a direct biological counterpart but here are intended to capture the fact that progressive maturation implies a time delay, in line with previously published implementations of neutrophil maturation models. Once maturation is completed, cells are stored in a bone marrow reservoir pool, awaiting egress into peripheral blood circulation. Circulation pool represents circulating neutrophils (i.e., level of neutrophils in blood, comparable to clinical ANC). Finally, circulating neutrophils are subjected to terminal elimination (cell death)