Pharmacokinetic And Pharmacodynamic Considerations

When a drug is administered, it is readily distributed to various compartments by blood. The relative amounts of drug available at the target (response compartment) and nontarget (toxicity compartment) sites determine the therapeutic effect and toxicities relative to that effect. In conventional therapy, the natural distribution characteristics of the drug determine the ratio of therapeutic response to the toxic effects.

Targeted drug delivery systems are designed to maximize therapeutic response by delivering a drug selectively to its pharmacological site(s). Several factors determine the availability of a drug at the target site (82,83). These include the rates of (i) input of targeted drug into the body plasma, (ii) distribution of targeted drug to the active site, (ii'i) release of active drug from the targeted drug at the site of action, (iv) removal (elimination) of the targeted drug and free drug from the target site, (v) diffusion or transport of the targeted drug and free drug from the active site to nontarget sites, and (vi) blood and lymph flow to and from the target site. The release of free drug from the targeted drug delivery system may occur either passively or by an active mechanism mediated by an internal or external stimulus (e.g., pH, temperature, and enzymes). In enzyme-mediated mechanisms, the rate of release of free drug depends on the activity and concentration of the enzyme involved, whereas in processes that are selective but nonspecific to the local chemical characteristics of the active site, the rate of release of drug varies with the concentration of the targeted drug available at the site. Thus, depending on the rate of distribution of targeted drug delivery to active site(s) and the rate of elimination of targeted drug from the active site (with respect to the rate of delivery to this site), a drug may or may not be available at the target site in sufficient amounts to produce the desired pharmacological effect (82). The rate of distribution of targeted drug delivery system to the target site depends on the rate of blood flow, whereas the permeability of endothelium, the rates of blood and lymph flow to and from the target site, and the rate of release of free drug determine the removal of targeted delivery and free drug from the active site. The product of blood flow and concentration of the species in the blood provides the upper limit of distribution of targeted drug or free drug to a specific tissue or organ in the body. The inability of macromolecules or charged species to cross membrane barriers can limit their access to and removal from the target sites. The binding of the targeted drug delivery system or drug within the target site reduces the concentration available for removal. Thus, for drugs that are active only in the free form, the binding reduces the effective amount required to produce the desired therapeutic effect.

On the basis of the assumption that the transport of targeted drug delivery from the target site to the rest of the body occurs by diffusion, convection or transport processes, Levy (84) predicted that drug elimination from the target site will be much more rapid than drug elimination from the body as a whole, the duration of the bolus dose administration will be much shorter than that of the conventionally administered dose, and the rate of elimination of targeted drug from the site of action will not be affected by changes in biotransformation and excretion kinetics or other processes, such as the liver perfusion rate, that determine the systemic clearance of a drug. Further, if there is a large difference between the rates of drug elimination from the active site and that from the body, if the ratio of the effective dose at the active site to that in body plasma is small, and if elimination at the target site does not represent biotransformation, then the drug in the body will gradually accumulate if the targeted drug delivery system is continuously administered. As a result, the pharmacological effect will gradually increase. However, because the drug amount in the body plasma will continue to increase, the drug-targeting selectivity may be lost. Thus, to maintain the selectivity of drug targeting, the drug delivery system must be designed such that it provides a very low continuous input relative to the rate of elimination of drug from the body (84).

In conventional delivery, the pharmacological response of a drug is assumed to be linearly related to the drug concentration in the plasma. This relationship between concentration and effect is much more complex in targeted drug delivery. It can vary in different organs or tissues, depending on access, retention (maintenance of adequate levels of targeted delivery and free drug at the active site), and timing of release of drug within the site. The various approaches used to quantitate targeted drug delivery systems have been reviewed by Gupta and Hung (85). These authors suggested that the overall drug-targeting efficiency (Te*), which represents selectivity of a delivery system for the target tissue (T), compared with n nontarget tissues (i), can be reliably calculated according to the following expression:

t (AQU?)t x (weight or volume) T Te = E"=i (AQuo')i x (weight or volume),.

where (AQU^)T is the area under the amount of drug (0 in a tissue versus time curve. Q can be obtained, at any time t, by the relationship Q = C-V(orC-W), where C is the concentration of drug at time t, and V and W are the volume and weight, respectively, of the tissue.

A comprehensive discussion of pharmacokinetic/pharmacodynamic modeling in drug targeting has been recently reviewed in a book chapter by Proost (86).

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