Drug Targeting Organ-Specific Strategies

13.5 Evaluation of Effectiveness of Drug Targeting Using PK and PK/PD Modelling 361
the DTI. Therefore the criticism of Siegel et al. [45] does not seem relevant for the appreciation
of the DTI. It should be noted that the equations for the DTI in several references
[7,44,48] are seemingly different from Eq. 31.24, by using the clearance from the non-target
sites instead of the total body clearance. In fact, these equations are identical after appropriate
rearrangements.
Apart from drugs directed at hepatocytes and renal tubular cells, in the case of the majority
of conventional drugs, it is likely that the drug is not eliminated directly from the target
site, and therefore E R = 0, which further simplifies Eq. 13.24 to:
Eq. 13.25 is a more convenient form of Hunt’s equation (16) [6].
13.5.2 Implications of the DTI Concept
DTI = 1 + CL
Q R
(13.25)
The simplicity of Eq. 13.25 is striking: the DTI is determined by only two parameters.This can
be understood qualitatively from the following reasoning. The total dose of the drug is delivered
at the target site. If the drug did not leave the target compartment (that is, Q R = 0), the
drug concentration at the target site would remain constant, and the DTI would be infinitely
high. The faster the removal of the drug from the target site (increase of Q R), the lower the
AUC at the target site, and the higher the AUC at non-target sites, including the toxicity site,
and thus the DTI is lowered. If there is no clearance of the active drug (that is, CL = 0), it
would eventually distribute evenly over the body, and there would be no net drug targeting
effect (DTI = 1). The faster the removal of the drug which is present outside the target site
(increase of CL), the lower the concentration and the AUC in the non-target compartments,
including the toxicity compartment, and thus the higher the DTI.
The impact of Eq. 13.25 can be rather impressive, as was demonstrated in the paper of
Hunt et al. [6]. These authors evaluated Eq. 13.25 by expressing both CL and Q R as percentages
of the cardiac output (normal value for an adult man 5 l min -1 ). The total blood flow
through the liver (1.5 l min -1 ) and kidneys (1.2 l min -1 ) is 54% of the cardiac output. Since a
high extraction ratio in both the liver and the kidneys is unlikely, a clearance corresponding
to 40% of the cardiac output may be considered as a maximum value for drugs eliminated by
liver and kidney (for drugs eliminated by other mechanisms, a higher value might be possible,
however). If we postulate that a DTI value of 5 is a minimum for a successful targeting
strategy, it follows that for a drug with a clearance of 40% of the cardiac output, the blood
flow through the target organ must be lower than 10% of the cardiac output in order to obtain
sufficient targeting efficiency. The upper limit for Q R is even lower for drugs with a lower
clearance, and decreases further rapidly in the more realistic cases where the drug carrier
is not ideal. For a detailed analysis see Hunt et al. [6].
In conclusion, drug targeting to tissues that receive a relatively large fraction of the cardiac
output is unlikely to create effective targeting if transport of the free drug to and from the
target cell can occur. Particularly after multiple dosing, a steady state will be reached in which
the increase in free drug concentration in the target tissue compared to that in the plasma
and that in the toxicity related tissue, will be moderate.