Drug-carrier conjugates

Rnally, pharmacokinetic and pharmacokinetic/pharmacodynamic modelling can be used for the purpose of prediction of the concentration-time profile of the drug and drug-carrier conjugate after repeated administration from single dose data, as well as for the prediction of the dose needed to maintain the concentration at the target site within a therapeutic window. 

For the sake of simplicity, in this chapter it is assumed that both the drug-carrier conjugate and the drug carrier itself, or the pro-drug, do not exert any pharmacologic or toxicologic ef-... 

The transport mechanisms that operate in distribution and elimination processes of drugs, drug-carrier conjugates and pro-drugs include convective transport (for example, by blood flow), passive diffusion, facilitated diffusion and active transport by carrier proteins, and, in the case of macromolecules, endocytosis. The kinetics of the particular transport processes depend on the mechanism involved. For example, convective transport is governed by fluid flow and passive diffusion is governed by the concentration gradient, whereas facilitated diffusion, active transport and endocytosis obey saturable MichaeUs-Menten kinetics. 

Figure 13.3. Model of Stella and Himmelstein, adapted from reference [5] (Section 13.3.1). The drug-carrier conjugate (DC) is administered at a rate i c(DC) into the central compartment of DC, which is characterized by a volume of distribution Fc(DC). DC is transported with an inter-compartmental clearance CLcr(DC) to and from the response (target) compartment with volume Fr(DC), and is eliminated from the central compartment with a clearance CZ.c(DC). The active drug (D) is released from DC in the central and response compartments via saturable processes obeying Michaelis-Menten kinetics defined by Fmax and Km values. D is distributed over the volumes Fc(D) and Fr(D) of the central and response compartment, respectively. D is transported with an inter-compartmental clearance CLcr(D) between the central compartment and response compartment, and is eliminated from the central compartment with a clearance CLc(D).

Hunt et al. [6] introduced the term Therapeutic Availability as the ratio of the fraction of the dose reaching the target sites, if the dose is administered as the drug-carrier conjugate, to the fraction of the dose which reaches the same sites if an equal dose of the active drug is administered intravenously, as formulated below. 

Hunt et al. [6] also introduced the Drug Targeting Index, which was defined as the ratio of drug delivered to the target and toxicity sites when the drug-carrier conjugate is administered, divided by the same ratio when the active drug is administered intravenously and is formulated as follows. 

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]. 

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... 

Binding of drug or drug-carrier conjugate to plasma proteins and various other non-target tissues [46,55], which potentially act as a slow release compartments (see Section 13.2.1.4). 

Allen C, Eisenberg A, Maysinger D (1999a) Copolymer drug carriers Conjugates, micelles and microspheres. STP Pharma Sci 9 139-151... 

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