Drug Targeting Organ-Specific Strategies

350 13 Pharmacokinetic/Pharmacodynamic Modelling in Drug Targeting
13.3 Pharmacokinetic Models for Drug Targeting
In 1980, Stella and Himmelstein [5] introduced the principles of pharmacokinetic modelling
into the field of pro-drugs and site-specific delivery. In 1986, Hunt et al. [6] extended the model
of Stella and Himmelstein by taking into account a specific area where toxicity occurs.
Their work may be considered as the frame of reference for later work in this area.
13.3.1 Model of Stella and Himmelstein
The model of Stella and Himmelstein [5], depicted in Figure 13.3, was originally derived for
pro-drugs, and may be considered as a minimal model for evaluating the pharmacokinetics of
pro-drugs and drug targeting systems. Since the drug–carrier conjugate (DC) and the active
drug (D) are different entities, and since the model should be able to discriminate between
the target site and non-target sites, a pharmacokinetic model for drug–carrier conjugates
should include, at least, the following compartments (Figure 13.3):
RC(DC)
DC
response (target)
compartment
VR(DR)
DC
central
compartment
VC(DR)
CLC (DC)
Vmax R
Km R
Vmax C
Km C
D
response (target)
compartment
VR(D)
CLCR(DC) CLCR(D)
D
central
compartment
VC(D)
CLC (D)
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 R C(DC) into the central compartment of DC,
which is characterized by a volume of distribution V C(DC). DC is transported with an intercompartmental
clearance CL CR(DC) to and from the response (target) compartment with volume
V R(DC), and is eliminated from the central compartment with a clearance CL 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 Vmax and Km values. D is distributed over the volumes V C(D)
and V R(D) of the central and response compartment, respectively. D is transported with an intercompartmental
clearance CL CR(D) between the central compartment and response compartment, and
is eliminated from the central compartment with a clearance CL C(D).