Safety assessment observation

In risk characterization, step four, the human exposure situation is compared to the toxicity data from animal studies, and often a safety -margin approach is utilized. The safety margin is based on a knowledge of uncertainties and individual variation in sensitivity of animals and humans to the effects of chemical compounds. Usually one assumes that humans are more sensitive than experimental animals to the effects of chemicals. For this reason, a safety margin is often used. This margin contains two factors, differences in biotransformation within a species (human), usually 10, and differences in the sensitivity between species (e.g., rat vs. human), usually also 10. The safety factor which takes into consideration interindividual differences within the human population predominately indicates differences in biotransformation, but sensitivity to effects of chemicals is also taken into consideration (e.g., safety faaor of 4 for biotransformation and 2.5 for sensitivity 4 x 2.5 = 10). For example, if the lowest dose that does not cause any toxicity to rodents, rats, or mice, i.e., the no-ob-servable-adverse-effect level (NOAEL) is 100 mg/kg, this dose is divided by the safety factor of 100. The safe dose level for humans would be then 1 mg/kg. Occasionally, a NOAEL is not found, and one has to use the lowest-observable-adverse-effect level (LOAEL) in safety assessment. In this situation, often an additional un-... 

A governing principle of pharmaceutical safety assessment is the determination of safety factors the ratio between the therapeutic dose (that which achieves the desired therapeutic effect) and the highest dose which evokes no toxicity. This grows yet more complex (but has less uncertainty) if one bases these ratios on plasma levels rather than administered doses. Traditionally based on beliefs as to differences of species sensitivity, it has been held that a minimum of a five-fold (5X) safety factor should be observed based on toxicity findings in nonrodents and a ten-fold (10X) based on rodents. 

This approach appears somewhat irrational and without much scientific merit, since many of these new molecules are minimally toxic or nontoxic by this sort of acute evaluation. As in the case of interferons or monoclonal antibodies, the toxic effects observed in humans might not be predicted from safety assessments in rodents. An appropriate test species should be selected. Is the rat or mouse the appropriate species to evaluate a species-specific rDNA protein such as human growth hormone or interferons, or would nonhuman primates be more suitable Does the nonhuman primate really offer any advantages There is some consensus that the nonhuman primate may be a more appropriate species for testing some rDNA human proteins. 

Study Type. Metabolic and pharmacokinetic data from a rodent species and a nonrodent species (usually the dog) used for repeat dose safety assessments (14 days, 28 days, 90 days or six months) are recommended. If a dose dependency is observed in metabolic and pharmacokinetic or toxicity studies with one species, the same range of doses should be used in metabolic and pharmacokinetic studies with other species. If human metabolism and pharmacokinetic data also are available, this information should be used to help select test species for the full range of toxicity tests, and may help to justify using data from a particular species as a human surrogate in safety assessment and risk assessment. 

Elderly No overall differences in safety were observed between subjects 65 years of age or older and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the efficacy of levetiracetam in these patients. Because elderly patients are more likely to have decreased renal function, take care in dose selection it may be useful to monitor renal function. 

Screening hundreds of compounds against 80-100 targets/year is an expensive research endeavor Ho vever, it is one of the crucial parts of predinical safety assessment and is also required by regulatory authorities [9]. Beside a better understanding of compound bioactivity profiles, which in some cases can be reliably linked to clinically observed side effects, there is also a particular aspect of the generated data which makes it worthwhile to be analyzed in more detail. 

There are inherent scale limitations in the time and space dimensions covered by laboratory studies. The applicability of the near field geochemical models derived from laboratory observations have to be applied to long-term, large-scale situations like the ones involved in the safety assessment of nuclear waste repositories. Hence, there is a need to test the models developed from laboratory investigations in field situations that are related to the ones to be encountered in repository systems. 

Frequently, a simple approach of pH adjustment or cosolvent is not enough to achieve the target concentration. Cosolvents are often used in combination with pH adjustment to further enhance the solubility. Using this approach, Lee et al. (2003) observed that nearly 85% of PLzer, Ann Arbor discovery compounds (> 300) submitted for discovery and preclinical injectable formulation development in the year 2000 could be formulated by pH adjustment, cosolvent addition, or a combination of the two approaches. It was also observed that 11% of compounds were not formulatable using this approach, and another32% ofthe formulation used more than 55% cosolvent. The high solvent content can limit the pertinent safety assessment of lead compounds. Therefore, the synergistic combinations of pH adjustment and cosolvent are not sufLcient to develop commercially... 

Safety assessments in travoprost studies have included evaluation of visual acuity, pupil diameter, iris color, anterior chamber flare, conjunctival hyperemia, pulse, blood pressure, blood chemistry profiles, and urinalysis values. The observed adverse events have generally been mild to moderate and have resolved without treatment. Most of the side effects seen with latanoprost can occur with travoprost treatment. Conjunctival hyperemia induced by travoprost is clinically insignificant but generally more than that observed with latanoprost. 

---