Pharmacology, particularly pharmacokinetics and pharmacodynamics, have tradition- ally influenced drug delivery formulations. Some of the newer developments in phar- macology and therapeutics that influence the development of DDSs are as follows:
1. Pharmacogenetics 2. Pharmacogenomics 3. Pharmacoproteomics 4. Pharmacometabolomics 5. Chronopharmacology
The first four items are linked together and form the basis of personalized medicine, which will be discussed later in this chapter.
4.1 Pharmacogenetics
Pharmacogenetics, a term recognized in pharmacology in the pregenomic era, is the study of influence of genetic factors on action of drugs as opposed to genetic causes of disease. Now it is the study of the linkage between the individual’s genotype and the individual’s ability to metabolize a foreign compound. The pharmacological effect of a drug depends on pharmacodynamics (interaction with the target or the site of action) and pharmacokinetics (absorption, distribution, and metabolism). It also covers the influence of various factors on these processes. Drug metabolism is one of the major determinants of drug clearance and the factor that is most often responsible for interindividual differences in pharmacokinetics.
The differences in response to medications are often greater among members of a population than they are within the same person or between monozygotic twins at different times. The existence of large population differences with small intrapa- tient variability is consistent with inheritance as a determinant of drug response. It is estimated that genetics can account for 20–95% of variability in drug disposition and effects. Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked. From this initial definition, the scope has broadened so that it overlaps with pharmacogenomics. Genes influence
pharmacodynamics and pharmacokinetics. Pharmacogenetics has a threefold role in the pharmaceutical industry, which is relevant to the development of personalized medicines. The three roles are as follows:
1. For study of the drug metabolism and pharmacological effects 2. For predicting genetically determined adverse reactions
3. Drug discovery and development and as an aid to planning clinical trials
4.2 Pharmacogenomics
Pharmacogenomics, a distinct discipline within genomics, carries on that tradition by applying the large-scale systemic approaches of genomics to understand the basic mechanisms and apply them to drug discovery and development. Pharmacogenomics now seeks to examine the way drugs act on the cells as revealed by the gene expression patterns and thus bridges the fields of medicinal chemistry and genomics. Some of the drug response markers are examples of interplay between pharmacogenomics and phar- macogenetics; both are playing an important role in the development of personalized medicines [18]. The two terms – pharmacogenetics and pharmacogenomics – are some- times used synonymously but one must recognize the differences between the two.
Various technologies enable the analysis of these complex multifactorial sit- uations to obtain individual genotypic and gene expression information. These same tools are applicable to study the diversity of drug effects in different popula- tions. Pharmacogenomics promises to enable the development of safer and more effective drugs by helping to design clinical trials such that nonresponders would be eliminated from the patient population and take the guesswork out of prescribing medications. It will also ensure that the right drug is given to the right person from the start. In clinical practice, doctors could test patients for specific single nucle- otide polymorphisms (SNPs) known to be associated with nontherapeutic drug effects before prescribing in order to determine which drug regimen best fits their genetic make-up. Pharmacogenomic studies are rapidly elucidating the inherited nature of these differences in drug disposition and effects, thereby enhancing drug discovery and providing a stronger scientific basis for optimizing drug therapy on the basis of each patient’s genetic constitution.
Pharmacogenomics provides a new way of looking at the old problems, i.e., how to identify and target the essential component of disease pathway(s). These changes will increase the importance of drug delivery systems, which need to be adapted to our changing concept of the disease. Drug delivery problems have to be considered parallel to all stages of drug development from discovery to clinical use.
4.3 Pharmacoproteomics
The term proteomics indicates PROTEins expressed by a genOME and is the systematic analysis of protein profiles of tissues. There is an increasing interest in
proteomics technologies now because deoxyribonucleic acid (DNA) sequence information provides only a static snapshot of the various ways in which the cell might use its proteins, whereas the life of the cell is a dynamic process. Role of proteomics in drug development can be termed pharmacoproteomics. Proteomics- based characterization of multifactorial diseases may help to match a particular target-based therapy to a particular marker in a subgroup of patients. The industrial sector is taking a lead in developing this area. Individualized therapy may be based on differential protein expression rather than a genetic polymorphism.
4.4 Chronopharmacology
The term chronopharmacology is applied to variations in the effect of drugs according to the time of their administration during the day. Mammalian biological functions are organized according to circadian rhythms (lasting about 24 h). They are coordinated by a biological clock situated in the suprachiasmatic nuclei (SCN) of the hypothalamus. These rhythms persist under constant environmental conditions, demonstrating their endogenous nature. Some rhythms can be altered by disease.
The rhythms of disease and pharmacology can be taken into account to modulate treatment over the 24-h period.
The knowledge of such rhythms appears particularly relevant for the understand- ing and/or treatment of hypertension and ischemic coronary artery disease. In rats and in man, the circadian rhythm of systolic or diastolic blood pressure can be dissociated from the rest-activity cycle, suggesting that it is controlled by an oscillator which can function independently of the SCN, which could justify modification of treatment according to the anomalies of the blood pressure rhythm. The morning peak of myo- cardial infarction in man is due to the convergence of several risk factors, each of which has a 24-h cycle: blood coagulability, BP, oxygen requirements, and myocar- dial susceptibility to ischemia. The existence of these rhythms, and the chronophar- macology of cardiovascular drugs such as nitrate derivatives, constitute clinical prerequisites for the chronopharmacotherapy of heart disease.
It is known that the sensitivity of tumor cells to chemotherapeutic agents can depend on circadian phase. There are possible differences in rhythmicity of cells within tissues. If cells within a tumor are not identically phased, this may allow some cells to escape from the drug’s effect. Perhaps synchronizing the cells prior to drug treatment would improve tumor eradication. Wild-type and circadian mutant mice demonstrate striking differences in their response to the anticancer drug cyclophos- phamide. The sensitivity of wild-type mice varies greatly, depending on the time of drug administration, while Clock mutant and Bmal1 knockout mice are highly sensi- tive to treatment at all times tested. Both time-of-day and allelic-dependent variations in response to chemotherapy correlate with the functional status of the circadian Clock/Bmal1 transactivation complex, which affects the lethality of chemotherapeu- tic agents by modulating the survival of the target cells necessary for the viability of the organism [19]. These findings will provide a rationale not only for adjusting the
timing of chemotherapeutic treatment to be less toxic but also for providing a basis for a search for pharmacological modulators of drug toxicity acting through circadian system regulators. This result may significantly increase the therapeutic index and reduce morbidity associated with anticancer treatment.
Chronopharmacological drug formulations can provide the optimal serum levels of the drug at the appropriate time of the day or night. For example, if the time of action desired is early morning, drug release is optimized for that time, whereas with conventional methods of drug administration, the peak will be reached in the earlier part of the night and with controlled release the patient will have a constant high level throughout the night. Effective chronopharmacotherapeutics will not only improve the efficacy of treatment but will open up new markets. This approach to treatment requires suitable drug delivery systems.
4.5 Impact of Current Trends in Pharmaceutical Product Development on DDS
Considerable advances have taken place in pharmaceutical industry during the past two decades. Contemporary trends in pharmaceutical product development that are relevant to DDS are listed in Table 1.10. Drug delivery technologies have become an important part of the biopharmaceutical industry. Drug delivery systems, pharmaceu- tical industry, and biotechnology interact with each other as shown in Fig. 1.1.
4.6 Impact of New Biotechnologies on Design of DDS
New biotechnologies have a great impact on the design of DDS during the past decade. The most significant of these technologies is nanobiotechnology.
Table 1.10 Current trends in pharmaceutical product development Use of recombinant DNA technology
Expansion of use of protein and peptide drugs in current therapeutics Introduction of antisense, RNA interference, and gene therapy Advances in cell therapy: introduction of stem cells
Miniaturization of drug delivery: microparticles and nanoparticles Increasing use of bioinformatics and computer drug design A trend toward development of target-organ-oriented dosage forms Increasing emphasis on controlled-release drug delivery
Use of routes of administration other than injections
Increasing alliances between pharmaceutical companies and DDS companies DDS drug delivery systems