Sarkar, Lauffenburger, 2003
Version 02 was created from Version 01 on 30/04/07 by James Lawson. The variable N was defined using an equation from the Sarkar and Lauffenburger 2003 paper. Version 03 was created from Version 02 by James Lawson on 01/05/07 and now includes the pharmacological simulations described in the paper. This file is known to read in PCEnv.
Currently, drug design and development takes, on average, 12 years and costs more than 800 million US dollars. Much of this time and money is spent on experiments and drugs that fail. There is very little mechanistic understanding as to how the various levels of biological complexity - from molecular interactions, to cellular function, to tissue organisation, to whole organs and beyond - are integrated. Hierarchical mathematical models provide a method for integrating this data. Specifically, in the model described here, Sarkar and Lauffenburger focus on the case of granulocyte colony-stimulating factor (GCSF).
GCSF is of great clinical importance, especially for cancer patients undergoing chemotherapy. The drug is injected into the blood stream where it then diffuses to the bone marrow and binds to its receptor GCSFR on precursor cells, inducing them to replicate and differentiate into mature neutrophils. In this way, the neutrophil count of immunocompromised patients is significantly increased. However, the bone marrow precursor cells engulf and degrade the GCSF, a negative feedback mechanism that reduces its potency. In addition, mature bone cells express the receptor GCSFR, and they bind, engulf and degrade the drug from the bloodstream. Thus, there is a significant negative feedback loop that reduces the lifetime of the drug.
The mathematical model developed by Sarkar and Lauffenburger relates extracellular GCSF depletion to the molecular properties of the ligand and the cells expressing the GCSF receptor (see the figure below). The authors then further integrated this cell-level model into a physiologically relevant pharmacokinetic/pharmacodynamic model.
The complete original paper reference is cited below:
Cell-Level Pharmacokinetic Model of Granulocyte Colony-Stimulating Factor: Implications for Ligand Lifetime and Potency in Vivo, Casim A. Sarkar and Douglas A. Lauffenburger, 2003, Molecular Pharmacology , 63, 147-158. (Full text (HTML) and PDF versions of the article are available on the Molecular Pharmacology website.) PubMed ID: 12488547
|Cell-level trafficking model for the GCSF/GCSFR system.|