Despite the pharmaceutical industry successfully identifying the active molecule against a certain disease target, many drugs still fail to enter the market mainly due to toxicity challenges. As such, the manufacturers have to assess the safety profile of the lead compounds during the drug development process. This poses a great challenge to the toxicologists (European Medicines Agency, 2001). The assessment protocol of the lead compound in most cases targets risk assessment and therapeutic margins, as opposed to eliminating the toxic risk. This is addressed by running comprehensive preclinical trials.
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Assessment of the Safety Profile of Lead Compounds
The identification of a lead compound in drug development is part of the preclinical drug development process. It is one of the most integral steps in connecting the laboratory based drug discovery with clinical, human trials. In an effort to identify the lead compound, rigorous transition process is employed between the discovery step and the preclinical development with initial testing involving tests on pharmacology and toxicology. Similarly before the preclinical trial transits into full clinical trial, other steps involving the viability of the lead compound and its safety profile are carried out (Wendler & Wehling, 2010). The process of assessing the safety profile of the lead compound in drug development involves the creation of drug substance or the component into a pharmaceutically active ingredient. What follows is the designing of the dosage that entails two steps of pre-formulation and formulation. Analysis of the component follows through common analytical and bio-analytical methodologies. This allows for an informed validation, which is a major step in the drug development. This also allows for determination of the metabolic and pharmacokinetic elements of the drug component. On verifying these elements, toxicology that encompasses the safety of the product, more so the pharmacological safety can now be determined before the drug enters the clinical trial phase (Testa, 2001).
The pharmaceutical industry attempts to assess the safety profile of lead compounds within the drug development process using non-clinical animal studies. This is usually more important for new products that have not been used in the market before (Ross, Gross & Krumholz, 2012). In reference to a drug development process such as of rosiglitazone, the protocol of preclinical studies as developed by the Food and Drug Administration (FDA) was done (Hearn, 2011). The pre-clinical data collected revealed that metformin, a lead compound din not show any special toxicological manifestations when studies were done using the conventional toxicology methodologies. The elaborate preclinical determination of the effect of rosiglitazone on the cardiovascular system did not yield comprehensive results. Therefore, just like with other drug trials; it was decided that the concerns would be addressed during the clinical trials. In determining the level of safety in a lead compound, the administration of the drug is through the different routes of intravenal, intraperitoneal, intramuscular and oral. This is in an effort to determine the effects of different rates of the drug bioavailability. With the intravenous route known to have the highest bioavailability concentration, drug administration through this route is highly recommended in determining drug component safety (Teitelbaum, Lave, Freijer & Cohen, 2010).
In analyzing rosiglitazone, intravenous doses of the drug’s human metabolite, M10, were injected into lab mice. However, they had no adverse effects. However, data on the activity of the drug on the PPAR receptors were not conclusively collected. In such cases, it would be only advisable to repeat the study in order to obtain an elaborate preclinical dimension. In case the lab animals, which were initially used to determine the safety of the drug component, are inconclusive; other animals that would increase sensitivity to the drug should be tried. For instance in rosiglitazone trials, rabbits and dogs were found to be highly sensitive to metformin in comparison to mice. The different routes of drug administration used on these animals had different results with the oral route showing toxicity levels of low magnitude. The duration of the preclinical trials is another important component of the assessment process. A long time would allow for comprehensive results should be taken. Some preclinical studies take years to give conclusive evidence on the level of safety of the lead component. At least one year was taken while carrying repeat dose studies on rosiglitazone using a variety of lab animals and concentrating on toxicity studies to certain organs in these animals (Vanderwall, et al, 2011).
Important data on toxicity in the safety profile assessment analyses the genetic toxicity, carcinogenicity, reproductive toxicity and environmental risks associated with the drug element under investigation (Brambilla, Mattioli, Robbiano & Martelli, 2011). The process would entail “in vitro tests” to determine mutagenicity in model bacteria; chromosomal effects in mammalian cells; and in vivo tests on lab animals. Carcinogenicity tests are carried out by such studies as inhibition of cell-cell communication or inhibition of cell death, characteristics associated with tumours. Reproductive toxicity tests are also carried out to determine the effect of the compound on the reproductive system. Emphasis is more on the effect of the drug on the foetal development and the associated malfunctioning or malformations (Lalita, et al, 2010). The rosiglitazone trials on this toxicity revealed only female infertility in cases where the drug was given in multiple doses. This was thus disregarded as clinically irrelevant since the level of dosage that could have such an impact on the human would have to be twice the recommended amount (Steven, Niessn, Kathy, 2007). Environmental, safety assessment risk of the lead drug compound is necessary. This ensures that if the compound is released into the environment, it would not result in any adverse effects. This also includes environmental effect of the drug as a result of disposal of the unutilized drug into the environment or emission emanating from its production. In developing the rosiglitazone, the metformin hydrochloride and maleate derivatives, two of the leading active compounds, no environmental risk was identified as a result of their use (Schwanstecher, 2011).
Translating Preclinical Safety Results to Humans
Animal studies are done in pharmaceutical drug development process to give valuable data on toxicity before the drug can be used in human applications. Animal models have over time been found to provide relevant data that can be extrapolated into a human setting (Smith & Marshall, 2011). Following a set of regulations, the researchers obtain preclinical data. When this data is interpreted, it is used by clinical researchers to determine the risks involved in exposing the same drugs to patients (Littman & Krishna, 2011). This is important before initiating the clinical trials. The process of determining the in vivo toxicity is lengthy and is based on elaborate experiments, historical and published research information and the rules governing the protocols of such nature of research (Robert, Junji, Stephanie & David, 2010). The preclinical toxicity models may involve the use of a few numbers of animals or many depending on the tests. The process of translating the data from animal studies into the human context involves complex steps. These steps include measurement of plasma levels of the lead compound and associated metabolites, and then comparing the same with data from clinical trials. This is to enable the researcher obtain the necessary safety margins of the drug under development (Friedman, Furberg & Demets, 2010).
The toxicity testing in preclinical level is important as it considers the important components of the human body systems. The tests today focus on such systems as the cardiovascular system. In such a test, pharmacological safety and histopathological toxicity levels are determined using the lab animals. Some animals may have less suitability in different tests and as such should be replaced to obtain the required results from the appropriate specie (Maynard, 2011). A drug such as the Rosiglitazone whose trials were carried on mice revealed no adverse effects on the cardiovascular system of the mice. Therefore, the trials proceeded into the clinical phases. It is no surprise that the drug resulted in a negative impact on health of many patients thereby increasing cases of cardiac arrests. Evaluation of toxicity in the bone marrow and such phenomenon as coagulation of blood cells is carried in a similar fashion in both preclinical and clinical trial phases. This helps in obtaining accurate results through the enhanced comparison of different specie concurrently (Xu & Urban, 2011).
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Another area of consideration in extrapolating data from animal models to humans is the safety of the gastrointestinal tract. Rodents are majorly used in such tests as the intestinal formulation matches that of humans. Many studies have shown a positive correlation between the responses of rodents to drugs administered via the oral route to that of humans (Koolen et al, 2012). The use of dogs also gives relatively conclusive results. Hepatotoxicity is among the most important indicators of drug safety, and many researchers are keen on data obtained from the hepatic system. The liver is an integral organ in drug metabolism and thus its ability to breakdown toxic compounds into less toxic compounds gives an indication in the direction of the research. Both the preclinical and clinical phases of drug development are concerned with analysis of liver enzymes. The analysis gives information on level or chance of hepatotoxicity and hepatic histopathology, data that can be used to predict the impact of a drug in the human body in relation to its activity in the animal models. Renal toxicity is also used in the translation process. The researchers analyse data on blood parameters such as creatinine, blood urea nitrogen and electrolyte balances. The endocrine system is also a target for analysis with hormone analysis being done by use of bio analytic methods (Marklund & Hollered, 2011). Preclinical toxicology data on the endocrine, immunologic and pulmonary systems is important to researchers in an effort to translate the preclinical safety results to humans (Gad, 2008).
Drug development is a lengthy process but rightly so since the result should be playing a curative role and not disease inducer. Safety is the major element of concern in drug development with the underlying certain toxicology component issues requiring to be fully addressed.
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