Drug Targeting Organ-Specific Strategies

13.3.3 Model of Boddy
Boddy et al. [7] extended the model of Hunt by incorporating the pharmacokinetic behaviour
of the drug–carrier conjugate, analogous to the model of Stella and Himmelstein. Therefore
this model, depicted in Figure 13.5, is suited to the evaluation of the time course profile of
drug concentrations in each compartment, in contrast to the model of Hunt. Also, they reduced
the model by incorporating the elimination compartment within the central compartment.
Furthermore, the model was simplified by assuming that the volumes of distribution
are the same for the drug–carrier conjugate and the active drug. It is assumed that the blood
flowing from the compartments carries the DC and D at concentrations equal to those within
the compartments. In this specific case, the inter-compartmental clearances for both DC
and D can be equated to the blood flow to the response and toxicity compartments. The authors
presented their model as a three-compartment model. However, since each compartment
may contain both the drug and the drug–carrier conjugate (which are treated as different
entities), it might be more appropriate to refer to it as a six-compartment model. Finally,
Boddy et al. [7] extended the model to a PK/PD model by incorporation of the pharmacodynamic
equations analogous to Eq. 13.9 describing the therapeutic and toxic effect. Therefore
this model is not only suitable for the evaluation of the effectiveness of drug targeting with
respect to drug concentrations, but also with regard to the balance between therapeutic and
toxic drug effects.
13.3.4 Model of Rowland and McLachlan
13.3 Pharmacokinetic Models for Drug Targeting 357
Rowland and McLachlan [46] also extended the model of Hunt to allow the evaluation of the
effect of a permeability barrier and plasma protein binding on drug uptake. The model of
Rowland and McLachlan is based on the work of Aubrée-Lecat et al. [47], who investigated
the influence of various parameters on the amount of a macromolecular drug taken up by the
target tissue. In the model of Rowland and McLachlan the target site (target tissue) consists
of three distinct sites: blood, interstitium, and cells. Although the paper refers mainly to regional
drug delivery (for example, intra-arterial injection), their model allows the evaluation
of the effect of a permeability barrier and plasma protein binding on the removal of the drug
from the target site, which may be a critical step in the effectiveness of drug targeting (see
Section 13.4). The influence of permeability and plasma protein binding is evaluated using
the DTI (Section 13.4.2) as a measure of effectiveness of drug targeting.
13.4 Measures of Effectiveness of Drug Targeting
For practical purposes, measures of the effectiveness of drug targeting are required. Such
measures have been derived based on the pharmacokinetic profiles of the drug targeting system
and that of the active drug.