Abstract
The pharmaceutical industry plays a major role in human health.It is responsible for developing and disseminating drugs aimed at restoring human health. As such, the industry establishes a protocol to ensure that the drug development process is carried out successfully. The major factors to consider in this process are the drug safety and efficacy. To ensure that the drug used is of the appropriate standard the industry attempts to assess the safety profile of lead compounds within the drug development process. This is effectively done through the use of well structured protocol involving the preclinical and clinical phases. Before the drug is utilized by humans, thepharmaceutical industry has in place strategies to translate preclinical safety results to humans.
Pharmaceutical Industry (Literature Review)
Introduction
Despite the pharmaceutical industry successfully identifying the active molecule against a particular disease target, many drugs still fail to enter the market mainly due to toxicity challenges. As such therefore, 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.
Assessing the Safety Profile of Lead Compounds
The toxicity screens mostly used to determine the safety of the lead compound include genotoxicity. This assessment tool is focused on determining the ability of the compound to induce genetic mutations or chromosomal damage on the organism’s DNA. During the drug development process, it is paramount to eliminate any agents that display genotoxicity characteristics. Most drug developers have for the longest time used bacterial mutagenicity to screen the target compounds. Due to complexities arising from using this model, it has become important to use mammalian cells (Vanderwall et al, 2011). The process would generally entail in vitro tests to determine mutagenicity in model bacteria, chromosomal effects in mammalian cells and in vivo tests in lab animals. The bacterial tests most commonly used include assays to determine mutations such as in the luminescent Vibrio fischerior the Ames test on the Salmonella typhimurium strains. The screening process has become more rapid with the use of in vitro micronucleus assay which permits prompt determination of the chromosome-damaging compounds. Automation of the process has made the process even more rapid. The advanced use of computer models to screen and predict potential genotoxicity through structural models, has also immensely contributed to success in the process. However, the model’s major shortcoming is the inability to predict metabolic processes (Robert, Junji, Stephanie & David, 2010).
Another common assessment done is on carcinogenicity; the ability of the compound to induce tumours. Early carcinogenic activity screening is necessary though complex. In most cases the test is carried out late in the drug development process with result mainly coming out after phase-III trials. The mechanism of carcinogenicity requires elaborate studies to explain. Due to these challenges, most drug developers have relied on genotoxicity screens to stop developing such compounds on the assumption that all carcinogens induce genotoxicity; however it has emerged that a significant number of non-genotoxic compoundsinduce tumours. The screens are carried out by such studies as inhibition of cell-cell communication or inhibition of cell death.These screens have however proved inadequate in applicability across all studies due to shortcomings such as varied endpoints in addition to diverse and poorly understood mechanisms(Lalita et al, 2010).
Reproductive toxicity is elemental in assessment of compound safety profiles. This entails determining the effects of the lead compound on the reproductive process more so the ability of the target compound causing foetal malformations. Assessment has always targeted embryonic development and other cellular assays. Using the whole-embryonic culture system, the effects on the embryo are determined through cultivating post-implantation mouse embryos in presence of the compound under analysis. Though complex, the method is very sensitive. It involves removing of the foetuses from the animals under study, a painstaking process that restricts its use in general screening. Owing to the ability of the method to identify compounds hitherto not known to have any teratogenic effects in vivo, it is generally applied in screening for compounds suspected to have no such effects with those known acting as control. The use of cellular assays lack in specifity and are therefore used within known classes of teratogenic compounds (Xu& Urban, 2011).
Assessment also includes study of target organ toxicity; damage of specific organ by systemically available drug metabolites. During drug development, this poses a great challenge especially with most studies being done in vitro. Determining organ specific toxicity from the molecular level is complex. To circumnavigate this challenge, drug developers have attempted use of in vitro grown cells from organs such as liver, heart, bone marrow, kidney, lung and skeletal muscles in an effort to identify and optimize the lead compound (Gad, 2008). This method is however very costly but it helps overcome the challenges associated with in vivo studies which are difficult to allow specific organ targeting. Local toxicity is also another assessment done to determine the direct effects of the lead compound at the application site.Effects such as dermatological irritation of the compound are studied. Modern research techniques continue to be developed to understand the toxicity mechanisms from the molecular level (Freese, 2005) . Biotechnology is facilitating the development of transgenic animals with specific reporter genes that will revolutionize safety profile assessment through cassette dosing of different compounds to effectively carry out short term in vivo studies (Dale, 2011).
Translating Preclinical Safety Results to Humans
Before drugs can be used in clinical applications, they undergo rigorous pre-clinical tests.This involves the use of animal and microorganism models with the studies being carried both in in vitro and in vivo settings (Marklund&Hillered, 2011). As such therefore, the data collected from the animal studies must be extrapolated into applicability in humans. The transfer of this research into human applications is described in the pharmaceutical world as translation.The main aim of using the animal models is to ascertain the efficacy and toxicity margins of the drug under development (Wendler& Wehling,2010). However, the transfer of data obtained from animal studies into the human context is faced by challenges arising from the difference in cell physiology, pathological manifestations and the cell culture models used. Since the animal models remain the most appropriate models for use in drug development, the researchers will continue to use them (Hoffman et al, 2012). Therefore, the pharmaceutical industry currently adopts different methods with which to translate preclinical safety results to humans. Before a drug component is introduced into the market for human use, it undergoes a lengthy process of analysis that can be broadly classified into two stages (Maynard, 2011).
These are the preclinical and the clinical phases. To ensure safety standards even before entering the initial clinical phase, the researchers use animal models to explore and establish the dose-response relationship. With this information, it will be possible to identify the dosage quantity that will give maximum biological activity by considering factors such as drug safety margin and other adverse drug reactions notable from the model animals (Craig & Walter, 2000). This will therefore encompass toxicology studies. The analysis also entails making tissue specific analysis to ascertain if the active ingredient can be compatible in different specie of mammals including humans. With such data, it will be possible to extrapolate the information and contextualize it to be relevant and applicable in humans. Efforts should be made to ensure that any adverse effects pronounced in the animal models are well analysed before the product can be used in humans even if it is under development process (Testa, 2001).
It is highly recommended that safety studies touching on the pharmacodynamics and pharmacokinetics of the compound under study be conducted before initiating clinical trials. Today the researchers follow a stringent battery of studies in conformance with the provisions of drug safety agencies such as the Food and Drugs Administration in the United States (Hearn,2011). Such studies investigate the effects of the drug component on cardiovascular, digestive, centralnervous and respiratory systems to scrutinize any potential adverse pharmacological effects on the physiological performance of the systems depending on the dose ranges under trial. The protocols are today more elaborate following past incidences where drugs that had been cleared for use in the market were found to cause adverse drug reactions. A case in point is the anti-diabetic drug rosiglitazone which was withdrawn from the market due to its association with an increased risk of heart attacks. The route of the drug administration is a major area the researchers have been focusing following drug failures and toxicity cases such as the fatal gastrointestinal motility (Koolen et al, 2012).
Safety of the drug component under study is also considered in reference to the renal urinary system since the drug metabolites are usually released via this system. To ensure thatall the toxicity and the related safety concerns mentioned are addressed adequately before drugs are introduced to humans, the studies are conducted in accordance with Good Laboratory Practices (Ross, Gross &Krumholz, 2012). To translate the preclinical safety results to humans, the non clinical studies are carried out over the longest time possible to ensure all toxicology issues are addressed before the errors are traced during the clinical phase. Any additional data that may not be obtained during the preclinical phase either through observation or suspicion may be clarified during the clinical trials (Smith &Marshall , 2011). On ascertaining about the safety of the drugs in preclinical studies, clinical trials are carried out to obtain more specific information on the efficacy of the drugs on humans (Van Spall, Toren, Kiss, Fowler, 2007). The trials are more elaborate and are carried out under strict authorities with approval from the government of the country in which they are done. The clinical trials are carried in four distinct phases with phase I focusing on screening for safety, Phase II establishes the testing protocol. Phase III also called the final testing is used on larger trial groups and if the drug is approved following this trial, it enters the phase IV where post approval studies are done before the drug can be released into the market (Vanderwall, et al, 2011).
Conclusion
Drug development is a lengthy process but rightly so since the end result should be playing a curative role and not disease inducer. Safety is the major element of concern in drug development with the underlying specific toxicology component issues requiring to be fully addressed.
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