An in vitro quantitative systems pharmacology approach for deconvolving mechanisms of drug-induced, multilineage cytopenias
Fig 1
Illustration of the difference between the IC50 value assessed directly from experimental data and model-based deconvolution of mechanisms explaining downstream inhibition.
The cartoon shows the percent inhibition of granulocyte-macrophage progenitors (GMP) cells at increasing doses of drug. The IC50 value derived from this experimental data represents the cumulative loss along the pathway leading to the formation of GMP, including drug impacts on the early progenitors, hematopoietic stem cells (HSC) and multi-potent progenitors (MPP). On the right, model-derived Emax and EC50 values represent the drug’s direct effect on cell-killing or anti-proliferation on individual cell types, including HSC, MPP and GMP. In the proposed modeling framework, it is possible to separate effects on a specific cell type, from propagated effects, such as loss of upstream progenitors. The color gradients above all curves represent the percent inhibition (red/yellow color) or percent decrease (blue/yellow color) and these colors are used in later figures.