Drug Targeting Organ-Specific Strategies

13 Pharmacokinetic/Pharmacodynamic
Modelling in Drug Targeting
Johannes H. Proost
13.1 Introduction
Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer
Copyright © 2001 Wiley-VCH Verlag GmbH
ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)
13.1.1 Drug Targeting and Effectiveness: The Role of Pharmacokinetics
The key issue in drug targeting is the improvement of the effectiveness of the intended drug
therapy in comparison to conventional drug administration. In the present context, effectiveness
is defined as the net benefit of drug administration, that is, the balance of the therapeutic
drug effect and any harmful effect, including minor and major side-effects and toxicity.
For the sake of simplicity, any harmful effect of the drug will be referred to as toxicity
throughout this chapter. Also, effectiveness may be defined in terms of the increased apparent
potency and/or therapeutic effect of the administered drug. A drug targeting system produces
a larger and/or more prolonged pharmacologic effect than an equimolar dose of the
free drug, and a lower single dose and/or dosing rate is needed to reach the same effect.
To demonstrate an improvement in effectiveness, relevant and reliable measures of the effect
of drug administration should be available. Generally speaking, the best measure of the
effectiveness of drug therapy should be a measure of the ultimate goal: the benefit to the patient.
Although this approach is conceptually sound and logical, in practice the leap between
the experimental development of drug targeting preparations and the ultimate benefit to the
patient is extremely large. First, the experiments in the early development phase of a drug are
usually carried out in small laboratory animals. Second, the pathogenesis in these animals is,
in general, different from that in the patient for whom the therapy is intended. Third, the
measures of effectiveness and toxicity may differ between laboratory animals and man. In
laboratory animals the range of potential parameters or end-points is practically not limited,
since the complete animal can be analysed after sacrifice. On the other hand, the eventual
goal of the therapy, efficacy in the patient, cannot be readily assessed in objective terms.
Despite limitations, the measurement of the effectiveness of drug therapy in laboratory
animals, for example, by the reduction in size of a solid tumour or decreased levels of surrogate
tumour markers, is indispensable for the development of drug targeting preparations.
However, during rational drug development it is not sufficient to ascertain that one drug
preparation is more effective than another, it is important to find out the reasons why this is
the case.This will enable the introduction of further improvements in the process of optimizing
the design of the drug preparation. In the understanding of the effectiveness of drug therapy,
pharmacokinetics (relating drug administration to drug concentration at the site of action)
and pharmacodynamics (relating drug concentration to drug effect) are essential elements
[1,2]. It should be stressed that PK and PK/PD modelling (Section 13.2) are essential