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Ligand Concentration

Ligand concentration, typically notated \(C_{SS,L}\) or \(C_{SS,L,compartment}\) in Assess models, is the steady-state concentration of a soluble ligand not bound to its drug or receptor. For the ligand concentration within the central compartment, this is the free ligand concentration within the plasma.

For multi-compartmental models, the peripheral compartment ligand concentration is the concentration of ligand within the interstitial spaces of the peripheral tissues outside the central circulatory system.

Ligand Concentration in Assess

The ligand concentration within the central compartment can be set based on measured values from plasma samples. Such data is typically generated using one of the following methods:

  • ELISA or other immunoassays
  • Mass-spectrometry

As the ligand concentration parameter represents free soluble ligand not bound to drug or receptor, take note of whether the assay measures total ligand or free ligand. For example, if the ligand is captured in an ELISA or ECLIA by an antibody, what is measured will depend on whether the epitope is masked when the ligand is bound to its soluble receptor. This information may not always be readily available.

Due to technical challenges in sampling the interstitial spaces of peripheral tissues, ligand concentrations in specific tissues are rarely measured or reported. Therefore, setting the ligand concentration for the peripheral compartment (\(C_{ss,L,peripheral}\)) or disease/tox compartments must be estimated from other available data. One approach that may be taken is setting \(C_{ss,L,peripheral}\) to be the same as measured plasma values \(C_{ss,L,central}\). This approach would make the following assumptions:

  • Any difference in production or metabolism of the ligand between compartmental tissues is not great enough to lead to differences in ligand concentration between the compartments
  • Physical restriction of the ligand distributing between compartments is minimal, and thereby does not lead to accumulation of free ligand in one compartment over the other

The impact of this assumption can be tested by scanning across different ranges of ligand concentrations.

Example: Setting \(C_{SS,L,central}\) Based on Values Measured in Plasma or Serum

Mean EGF concentrations
Image licensed under CC-BY 4.0. (Lemos-González et. al. 2007)

The mean levels of EGF in the serum across 45 healthy patients was measured to be \(917.4 \frac{pg}{ml}\) (Lemos-González et al. 2007). The molecular weight of EGF is 6048 Da (PubChem).

The concentration is:

\[ C_{ss,L,central} = 917.4 \frac{pg}{mL} * \frac{mol}{6048 g} = 0.152 nM \]


  1. Lemos-González, Y., Rodríguez-Berrocal, F. J., Cordero, O. J., Gómez, C., & Páez de la Cadena, M. (2007). Alteration of the serum levels of the epidermal growth factor receptor and its ligands in patients with non-small cell lung cancer and head and neck carcinoma. British Journal of Cancer, 96(10), 1569–1578.