Research and Development Strategies


of similar route and duration. These adverse effects can include dose-limiting pharmacodynamic effects or other toxicity. In practice, some effects in the toxic range (e.g. tremors or fasciculation during electrocardiogram recording) may confound the interpretation of the results and may also limit dose levels. Testing of a single group of subjects at the limiting dose, as described above, may be sufficient in the absence of an adverse effect on safety pharmacology end-points in the test species.


Study Limitations


Despite efforts to maximise the predictive value of pre-clinical studies, there will always be inherent limitations. These may include a general lack of understanding of the fundamental biochemical and physiological mechanisms that could help to better define appropriate parameters or the absence of the target site or receptor in the test species. There can also be significant differences in metabolic profiles across test species or difficulty in achieving sustained concentrations of the product at the target site or receptor(s). When relevant animal models of disease or relevant species are available, the data are generally more useful. However, it is worth bearing in mind that animals used in these studies are usually ‘normal’ or healthy. Extrapolation of the results of pre-clinical animal studies must therefore be considered not only across test species, but also across physiological states.


The Role of Pharmacokinetics


In each stage of product development it is important to determine exposure by measuring pharmacokinetic (including ADME) along with toxicology end-points. This measurement of pharmacokinetics in toxicology studies is referred to as toxicokinetics. This includes measurement of the drug in blood, plasma or target organs and the distribution and persistence in cells for cellular therapies.


Toxicokinetic studies provide important information for a better interpretation of the toxicity observed in animals. They aid in the selection of not only the proposed initial human dose, but also of the dose-escalation scheme and frequency of dosing in clinical trial(s). Once such exposure data are available in humans, the data can be used to better correlate the human and animal findings.


Toxicity studies should be performed in the same species used to assess exposure. Often exposure and toxicity are measured in the same study, particularly when non-rodents are used.


A biotechnology product can provide some unique considerations. Many biotechnology-derived pharmaceuticals intended for humans are themselves immunogenic in animals.4


Human cell-derived or


‘humanised’ molecules may cause immunotoxicity when administered to animals.5


The measurement of antibodies associated with


the administration of these types of products should therefore be performed when conducting repeated dose toxicity studies in order to aid in their interpretation. Antibody responses should be characterised (e.g. titre, number of responding animals, neutralising or non- neutralising) and their appearance should be correlated with any pharmacological and/or toxicological changes.


Specifically, when interpreting data, the following should be considered: the effects of antibody formation on pharmacokinetic/ pharmacodynamic parameters, the incidence and/or severity of adverse effects and complement activation.


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More drugs are now being studied in populations at both ends of the spectrum, since these are often significant populations that use many drugs. Such key patients include paediatric10 populations.11


and geriatric


Given the increasing use of drugs by these populations, pre-clinical studies may be needed to address matters in terms of their use in children and geriatric patients.


The purpose of pre-clinical testing is to select the starting dose and identify a dose that is expected to have pharmacological effects and be reasonably safe to use. The starting dose needs to be justified based on the non-clinical data available (e.g. pharmacokinetics, pharmacodynamics, toxicity) and its selection based on various approaches. For most systemically administered small molecules,


DRUG DEVELOPMENT


Specific toxicity studies may also be necessary due to special characteristics of the product or the clinical indication. For example, adjuvants used in vaccines are routinely evaluated for local reactivity and cellular therapies are routinely screened for tumourogenic potential. Products delivered by unusual routes of administration (such as intraophthalmic, topical, intravaginal, etc.) will require testing of the local toxicity of the product in the place and manner in which it is to be administered. In addition, research may be needed to better predict the sensitising potential of products and to determine the relevance of antibody levels following repeat dosing in animals and humans. The population that will ultimately use the drug also influences what types of toxicology studies may be required.6,7


Carcinogenicity studies are not performed routinely for many biological products. They are, however, appropriate and will be expected to be completed for traditional drug products proposed for chronic use.


Reproductive toxicology studies will commonly be completed, especially as more women of child-bearing potential are participating in clinical trials and products are increasingly being recommended for use in this population. Reproductive studies are not always conducted for biologic products, although they have been performed with many of the recently approved therapeutics (e.g. interferons, interleukins, cytokines, growth factors, etc.). Such studies also have been conducted in the development of HIV-related products intended for use in pregnant women.


Recently, much attention has been focused in the pre-clinical development phase on the ability to predict certain problems in humans. A key area of concern is the effect of different molecules on cardiac function, especially problems with cardiac rhythm. This is often manifested as a delay in the transmission of electrical impulses in the heart, as evidenced by QT prolongation. There now are a number of in vitro and animal studies that can be completed to try to predict the likelihood of this type of toxicity.8


Another area of consideration that has received more attention recently relates to drug-induced liver injury. The liver is the major organ in the body for drug metabolism, so if a drug effects the liver it can have a significant impact on how the body handles the drug as well as having an effect on many other drugs and natural compounds. Liver injury is relatively infrequent, but measurement of important liver enzymes can sometimes provide an early indication of potential problems.9


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