A comprehensive approach for drug safety assessment

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Abstract A comprehensive, multidisciplinary approach is proposed here for the development of a drug with an acceptable safety profile. Key parameters to be considered for drug safety evaluation based on this comprehensive approach include the following: (1) Pharmacology: Possible toxicity due to drug–target interactions, including interactions with unintended molecular targets, or with molecular targets in unintended organs. (2) Chemistry: Chemical scaffolding and side-chains with safety concerns. (3) Toxicology: Toxicity in animals in vivo, and in relevant animal and human cells in culture. (4) Drug metabolism and pharmacokinetics: Safety concerns due to toxification or detoxification, organ distribution, clearance and pharmacokinetic drug–drug interactions. (5) Risk factors: Physiological, environmental and genetic factors that may enhance a patient’s susceptibility. It is proposed that this integrated, multidisciplinary approach to safety evaluation may enhance the accuracy of the prediction of drug safety and thereby the efficiency of drug development. A comprehensive approach to drug safety evaluation The proposed comprehensive approach in drug safety evaluation is based on an integrated, multidisciplinary approach. This comprehensive understanding of drug safety should be applied towards all phases of drug discovery and development, from target identification through clinical trials. The key scientific disciplines to be included in this comprehensive approach to drug safety evaluation include pharmacology, chemistry, drug metabolism and toxicology. A new discipline of risk factor identification is also proposed. 2.1. Pharmacology As drugs are developed to be pharmacologically active, it is only logical that one should understand the safety concerns, if any, associated with the intended pharmacological effects. The toxicological ramification of the interaction of the drug candidate with the intended target in the target and nontarget tissues, and the likelihood of interactions with unintended targets, should be defined. This is especially important for a novel target with little preexisting clinical data. For instance, a novel target in the cell signaling pathways, which may have myriad cellular functions. Antagonists or agonists to a molecular target to cure a disease or to alleviate certain disease symptoms may lead to undesirable side effects due not only to the effects of the agent on the “normal” functions of the target but also the interactive cascade of events set off by engagement of the molecular pharmacology target, culminating in organ damage. Anticancer drugs represent where pharmacological effects can be related to drug toxicity. Recently, novel targets have been proposed for anticancer drugs based on the novel discoveries in tumor cell and molecular biology including molecular controls of cell division, apoptosis, macromolecular processing, invasion and angiogenesis. As many of these molecular targets are also present in nontumor tissues, one needs to assure that the unintended toxicity in normal tissue is significantly less than that in the cancer cells, or at least develop a rationale for why the target remains an appropriate target even though toxicity to normal tissues is likely to occur. An interesting case of an unintended pharmacologyrelated adverse effect is associated with the biologic infliximab—a monoclonal antibody against tumor necrosis factor (TNF), indicated for the treatment of rheumatoid arthritis and Crohn’s disease. The inhibitory effects of infliximab on macrophage activation are the mechanism for its desired anti-inflammatory effects. However, diminished macrophage activities cause an increased susceptibility of the patients towards infection. A warning was added to infliximab in 2001 for the following reason as stated in a letter from the manufacturer to healthcare professionals: “...The Box Warning was added as a result of the occurrence of 84 cases of tuberculosis worldwide, during the period from August 24th, 1998, through June 30th, 2001 ... An increased risk of infections associated with tumor necrosis factor blockade, is consistent with the known effects of TNF on macrophage activation and granuloma formation.” One should also anticipate possible drug–drug interactions based on pharmacological properties. A recent case of pharmacological drug–drug interaction is the interaction between sildenafil, a drug for erectile dysfunction. Sildenafil acts via the inhibition of cGMPspecific type 5 phosphodiesterase (PDE5). It also produces mild decreases in systolic and diastolic blood pressure and an array of minimal side effects, probably due to the inhibition of other types of phosphodiesterase. Drug interactions involving the concurrent use of sildenafil with nitrates and nitrites can produce profound hypotension leading to decreased coronary perfusion and myocardial infarction. A May 1998 letter from the drug manufacturer warns that the drug is not to be co-administered with organic nitrates. This potentially fatal drug interaction also led to the withdrawal of several sildenafil-containing herbal medications from the market. A conscientious effort to evaluate pharmacologically related adverse drug effects should allow one to avoid the selection of a problematic target and to identify management strategies early on to eliminate unexpected postmarketing adverse events. 2.6. Implementation The proposed comprehensive approach allows one to assess drug safety intelligently and scientifically, and therefore should be an integral part of the drug discovery and development process, from target selection to clinical trials. Drug candidates conscientiously selected based on the implementation of this approach should have a higher probability of clinical success than drugs selected based mainly on efficacy alone. This comprehensive approach is best practiced by a team with members with in depth knowledge of the multiple scientific disciplines described (pharmacology, chemistry, drug metabolism, pharmacokinetics, toxicology, genetics). An example of a Comprehensive Drug Safety Evaluation Team is one led by a toxicologist, with team members with expertise in pharmacology, chemistry, drug metabolism/pharmacokinetics, pathology, genetics and supplemented by other scientific disciplines as needed. Two major objections to the adoption of this comprehensive approach to drug safety evaluation are as follows: 1. Complications with regulatory approval: The old adage in regulatory toxicology is to present the regulatory agencies with the “cleanest” data package possible. Experimentations that may “complicate” the package are to be avoided at all costs. The price to pay for this approach is that data interpretations based purely on standardized, routine tests, without further investigative experimentations, may not allow one to accurately predict human drug safety. An investigative approach allows the presentation of scientific information and the rationale of the conclusion based on experimental data. It is argued here that via objective and scientific experimental approaches and data analysis, a drug candidate that is concluded to be safe to humans should rightly receive regulatory approval, and is in fact a more effi- cient approach than the current approach of a minimum data package and optimistically interpreting adverse data.