Drug Targeting Organ-Specific Strategies

354 13 Pharmacokinetic/Pharmacodynamic Modelling in Drug Targeting
tive drug levels are maintained at the site after administration of relatively low maintenance
doses of the drug targeting system. Obviously, a low, but substantial, rate of active drug removal
is a prerequisite for controlling the intensity and duration of the drug effect.
13.3.1.5 Release of D at Non-target Sites
The release or activation of a drug at non-target sites is the undesirable counterpart of release
at the target site (see Section 13.3.1.3), determining the selectivity of the release or activation
of the drug, and thus of the drug targeting.
In principle, the release at non-target sites can be measured by the same methods as used
for the target site (Section 13.3.1.3). In practice, however, measurement must be limited to
one or more selected cell lines, which do not necessarily include all the non-target sites in
which the drug may be released outside the intended target tissue.
13.3.1.6 Disposition of D
The distribution and elimination characteristics of the active drug have a profound influence
on the efficiency of drug targeting. This topic is dealt with in Section 13.5.
13.3.2 Model of Hunt
Hunt et al. [6] extended the model of Stella and Himmelstein by adding two compartments,
that is, a specific area where toxicity occurs, and an elimination compartment consisting of
the liver and kidney (Figure 13.4). Their model may be regarded as a simplified physiologically-based
pharmacokinetic model (Section 13.2.4.2). It is assumed that the drug concentration
in the blood or plasma (whichever is the reference fluid) exiting the compartments is a
function of the concentrations within the corresponding compartments. This implies that tissue
perfusion rather than permeability of the drug between blood and tissue is assumed to be
the rate-limiting step of the transport between the central compartment and each of the other
compartments (Section 13.2.1.3).
The model does not use a pharmacokinetic model for the drug–carrier conjugate. Instead,
the release of the active drug is modelled as an input function in each of the four compartments:
‘blood’ (central compartment), ‘response’ (target site), ‘toxicity’, and ‘elimination’.
The aim of their model was the derivation of the Therapeutic Availability (TA, Section
13.4.1) and the Drug Targeting Index (Section 13.4.2). For the particular derivations, several
simplifications were made; for example, the aforementioned drug input replaces the model
for DC. As a result, their simplified approach cannot be used for the prediction of the time
course of the drug concentrations in the various compartments. This limitation does not affect
the ability of the model to evaluate steady-state drug concentrations, which can also be
used as an appropriate measure of the average concentration over a single dose interval after
repeated administration. However, their analysis does not give insight into the time
course of drug action, that is, the time needed to reach steady state, and the duration of the