Drug Targeting Organ-Specific Strategies

efers to administration of the drug–carrier conjugate, and D to the intravenous administration
of the active drug.
The concept of DTI is based on a pharmacokinetic model analogous to the model shown
in Figure 13.4. Boddy and Aarons [44] used a simplified model, corresponding to Figure 13.3,
in which the toxicity sites are included in the systemic (non-target) tissues, and the formula
for DTI should be modified accordingly.
Comparing Eq. 13.20 and Eq. 13.23, it follows that the DTI is equal to the ratio of the Therapeutic
Availability at the target site (Eq. 13.20 or 13.21) and the corresponding equation for
the toxicity site. In the case of an ideal carrier, that is, if the drug is released only, and completely,
at the target site, and if the target site does not contribute to the elimination of the
drug, the value of the DTI is identical to that of TA [6].This could be inferred from the recognition
that the AUC at the toxicity sites, after administration of the drug–carrier conjugate, is
the same as that after intravenous administration of the same dose of the free drug.
Hunt et al. [6] demonstrated that the DTI is also equivalent to the ratio of the therapeutic
index (abbreviated to TI in Hunt et al.’s paper; in this chapter TI is defined differently, see
Section 13.4.3) of the drug–carrier conjugate and that of the free drug.The therapeutic index
(also called the therapeutic ratio) is a statistical measure defined as the ratio of the median
toxic dose to the median effective dose [22].
Hunt et al. [6] considered the DTI the best measure of the effectiveness of the carrier.
13.4.3 Targeting Index (TI)
Boddy et al. [7] introduced the term Targeting Index as the ratio of the toxic effect when a
drug–carrier conjugate is administered divided by the toxic effect when the free drug is given
intravenously at a rate producing the same drug concentration (and thus the same drug effect)
in the target site.
The Targeting Index is the ‘effect’ analogue of the Drug Targeting Index, which can be defined
as the ratio of the drug concentration in the toxicity compartment when a drug–carrier
conjugate is administered divided by the drug concentration in the toxicity compartment
when the free drug is given intravenously at a rate producing the same drug concentration
(and thus the same drug effect) in the target site; this definition is equivalent to Eq. 13.23.
Note that Hunt et al. [6] used the abbreviation TI for the Therapeutic Index (see Section
13.4.2).
13.5 Evaluation of Effectiveness of Drug Targeting Using PK
and PK/PD Modelling
13.5.1 Effectiveness of an Ideal Carrier
13.4 Measures of Effectiveness of Drug Targeting 359
An example of the application of the model of Boddy is depicted in Figure 13.6, showing the
concentrations of active drug in the response and toxicity compartments after repeated administration
of an hypothetical drug–carrier conjugate.After the first dose the concentration