Drug Targeting Organ-Specific Strategies

368 13 Pharmacokinetic/Pharmacodynamic Modelling in Drug Targeting
ready been stated by Hunt et al. in 1986 [6], their message did not seem to be understood by
many researchers, given the enormous volume of literature on the targeting of conventional
drugs with a relatively low clearance rate. The fact that this basic premise does not seem to
have been acknowledged by research workers in this area, may well be related to the limited
number of successful drug targeting procedures which have been reported thus far.
Looking to the future, the newer generation of therapeutic peptides that have been identified
using molecular biology technology rather than classical pharmacology, including protein
drugs, antisense oligonucleotides and plasmid DNA, are excellent candidates for drug
targeting, for at least three reasons. First, targeting may be necessary for this type of compound
to reach the target sites, due to their physicochemical properties. Second, the clearance
rate of these compounds is generally high, and therefore the DTI will be high.Third, the
high clearance rate requires frequent dosing to maintain a therapeutic effect, and large doses
to compensate for the high loss of the drug. Drug targeting may significantly increase the
duration of action and the apparent potency.
In addition, the successful application of drug targeting to this new generation of drugs
may provide the impetus for further research and development, since well-designed drug targeting
strategies may be used for the delivery of potentially therapeutic compounds which
cannot be utilized in the currently available conventional drug delivery systems. The results
of future developments may challenge researchers in every discipline involved in drug development.
In the field of PK and PK/PD modelling, the newer generation of drugs provide opportunities
to extend the area of research. These newer drugs may also raise many problems, for
example in the analysis of these compounds in tissues. This is particularly true in relation to
the selectivity of assays towards inactive or active metabolites, and with respect to the levels
of sensitivity required to detect very small amounts of highly active compounds. Also, PK
modelling may become more detailed with respect to the target and toxicity sites. Physiologically-based
PK/PD modelling may be necessary to evaluate the effectiveness under changed
(patho-)physiological conditions (for example, changes in blood perfusion or pH of the target
site, changes in receptor density and the development of tolerance). PK and PK/PD modelling
are valuable tools for quantifying the beneficial effects of changes in the construction
of drug–carrier conjugates, including the optimization of dosing schedules for such sophisticated
drug targeting systems.
In conclusion, it may be expected that further development of PK and PK/PD will contribute
to the successful development of new drug targeting products.
References
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[2] Suzuki H, Nakai D, Seita T, Sugiyama Y, Adv. Drug Deliv. Rev. 1996, 19, 335–357.
[3] Breimer DD, J. Drug Target 1996, 3, 411–415.
[4] Hoffman A, Adv. Drug Deliv. Rev. 1998, 33, 185–199.
[5] Stella VJ, Himmelstein KJ, J. Med. Chem. 1980, 23, 1275–1282.
[6] Hunt CA, MacGregor RD, Pharm. Res. 1986, 3, 333–344.
[7] Boddy A, Aarons L, Petrak K, Pharm. Res. 1989, 6, 367–372.
[8] Takakura Y, Hashida M, Pharm. Res. 1996, 13, 820–831.
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