Drug Targeting Organ-Specific Strategies

344 13 Pharmacokinetic/Pharmacodynamic Modelling in Drug Targeting
(Note the typing errors in Nakai et al. [28]; in their equations 16 and 19, the second term
k SR should be replaced by k RS; similarly, in equations 17 and 20, the second term k RS should
be replaced by k SR).
13.2.5.3 Empirical PK/PD Relationships
Many empirical relationships between PK and PD have been described in the literature. Several
of these empirical relationships have been reviewed by Kobayashi et al. [29].
13.2.6 Pharmacokinetic/Pharmacodynamic (PK/PD) Models
PK/PD models are obtained by combining a PK model (Section 13.2.4) and a PD model (Section
13.2.5), allowing the quantification of the relationship between drug administration and
drug action.The principles of PK/PD modelling will be dealt with briefly. For a more detailed
treatise, some excellent reviews can be found in the literature [21].
Usually, the target compartment of the PK model is the site where the active drug is released.
If there is a negligible diffusion barrier between the site of drug release and the site
of drug action (effector site), the drug action (Eq. 13.9) is governed by the concentration in
the target compartment. In other cases the site of action may be more remote from the site
of drug release, and the concentration at both sites may be different due to a diffusion barrier.
In such cases, an extra compartment (effect compartment, effector site) can be added to
the model as a link between the ‘driving’ compartment (here, the site of drug release) and the
drug effect [23,24]:
dCe = ke0 · (C – Ce) (13.14)
dt
where C e is the drug concentration in the effect compartment, C is the concentration in the
driving compartment, and k e0 is the transfer rate constant between the effect compartment
and the driving compartment.
13.2.7 Simulations
If an appropriate model is selected and the model parameters are known, the time course of
the drug concentration in each compartment (PK models) and the drug effect (PK/PD models)
can be calculated for any dosing regimen. In addition, the relevant measures of the effectiveness
of drug targeting can be calculated (see Section 13.4).
Usually, the most appropriate model and values of model parameters are not known, in
which case, the relevant information is obtained from simulations with various models and
parameter values, based on reasonable estimates and on previously obtained experimental
data. Despite their limitations, such simulations can be helpful in drug design and development,
including the prediction and evaluation of drug targeting strategies. Using PK or
PK/PD models, the effect of drug targeting can be quantified, taking into account not only