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WIREs Syst Biol Med
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Network pharmacodynamic models for customized cancer therapy

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Pharmacokinetics (PKs) and pharmacodynamics (PDs) have always been integral to the design of rational drug dosing regimens. Early on PK‐driven approaches came under the auspices of therapeutic drug monitoring that progressed into population‐based PK and PK/PD modeling analyses. As the availability of tissue samples for measurement of drug concentrations is limited in patients, the bulk of such model‐based methods relied on plasma drug concentrations to both build models and monitor therapy. The continued advances in systems biology and the spawning of systems pharmacology propelled the creation of enhanced PD (ePD) models. One of the main characteristic of ePD models is that they are derived from mechanistically grounded biochemical reaction networks. These models are commonly represented as systems of coupled ordinary differential equations with the ability to tailor each reaction and protein concentration to an individual's genomic/proteomic profile. As patient genomic analyses become more common, many genetic and protein abnormalities can be represented in the ePD models, and thus offer a path toward personalized anticancer therapies. By linking PK models to ePD models, a full spectrum of pharmacological simulation tools is available to design sophisticated multidrug regimens. However, ePD models are not a panacea and face challenges in model identifiability, scaling and parameter estimation. Nonetheless, as new technologies evolve and are coupled with fresh ideas on model implementation, it is likely that ePD and PK/ePD models will be considered a viable enterprise to customize anticancer drug therapy. WIREs Syst Biol Med 2015, 7:243–251. doi: 10.1002/wsbm.1300 This article is categorized under: Translational, Genomic, and Systems Medicine > Translational Medicine
Hypothetical cell signaling pathways that form the basis of an enhanced pharmacodynamic (ePD) model. Each shape is a protein with the rectangles representing receptor tyrosine kinases within three parallel and interconnected ‘units’. The central unit is the drug target pathway. Should the ePD model be confined to the central unit or also include the two other units? This idealized network illustrates a potential problem in defining the boundaries of the model.
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(a) Optimization‐based control multidrug regimen applied to the VEGFR biochemical pathway for a 28‐day cycle. The five drugs available are shown in the legend. A relative dose of 0 is the lowest dose possible and a value of 1 the maximum defined from clinical data. (b) The corresponding pERK and pAkt profiles expressed as the fractional response. The profiles show some adulations – particularly for pERK – but both proteins met the 80% inhibition criteria set for the controller. (Reprinted with permission from Ref . Copyright 2014 ASCPT All rights reserved 2163–8306/12)
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Pipeline to construct and utilize PK/ePD models to design multidrug regimens. The parameter estimation, sensitivity analyses and optimization‐based controller steps are distinct computational steps and can be extensive. (Reprinted with permission from Ref . Copyright 2014 ASCPT All rights reserved 2163–8306/12)
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