Toxicology testing, nonclinical

All human circulating metabolites that account for >10% of the administered dose or systemic exposure (whichever is less) and that were not present at sufficient levels to permit adequate evaluation during nonclinical animal studies should be considered for additional safety/ toxicological testings. 

Like any other profession or scientific discipline, safety pharmacology has its beginnings, in terms of name, concepts, discipline, practices, philosophy, and specific tests. Gerhard Zbinden (1979) is generally credited with calling attention to the disconnect between the study endpoint (e.g., histopathology) of standard nonclinical toxicological test procedures of that era and the types of adverse dmg reactions (ADRs) observed by clinicians in clinical trials that whereas the former... 

Except for issues such as risk assessment and factors that would indicate the need to determine the potential effect of test article on immune function, the various guidelines are fairly consistent in what tests are recommended. ICH S8 contains a table suggesting the parameters that should be assessed in nonclinical toxicology studies these parameters do not differ significantly from other guidelines (see Table 2.1). The... 

Although, in the 1950s nonclinical safety testing was limited to rodents, with appropriate testing, malformations could be produced in that species and resorptions were a known indicator of possible teratogenesis. The separation of response in rats and rabbits with thalidomide formed the basis for reproductive toxicology guidelines used today. 

Tests to characterize a test or control article as to its identity may be postponed until initial toxicology studies show a reasonable promise of the article s reaching the marketplace. The FDA has indicated, however, that information on strength and purity should be available prior to the use of the article in a nonclinical laboratory study. 

If the systemic exposure for a major human circulating metabolite is equivalent to that observed in nonclinical toxicological species, then the metabolite levels may be sufficient to limit additional toxicity testing using the major human metabolite. 

Results of nonclinical laboratory studies, including microbiological, toxicological, immunological, biocompatibility, stress, wear, shelf life, and other laboratory or animal tests, including a GLP statement. 

Nonclinical pharmacokinetic investigation is helpful when interpreting the data from safety (pharmacological) studies, and it also provides support for toxicology studies. While nonhuman pharmacokinetic parameters are not perfectly predictive of human pharmacokinetics, they do constitute meaningful quantitative data that improve the chances of selecting the correct range of safe doses to test in humans. This dose selection is critically important to the success of clinical trials. 

Nonclinical research provides very useful information and plays a considerable role in the successful development of a new drug. It is also required by current regulatory statutes. Nonetheless, no matter how meticulously, rigorously, and comprehensively nonclinical testing is conducted, no animal model is a perfect model of the drug s actions and effects in humans. Therefore, in addition to an appreciation of the usefulness of nonclinical data, it is valuable to have an appreciation of their limitations and of statistical considerations of particular pertinence to toxicological data. 

Nonclinical Studies In vitro (laboratory) or in vivo (animal) pharmacology, toxicology and pharmacokinetic studies that support the testing of a product in humans. Usually at least two species are evaluated prior to Phase I clinical trials. Nonclinical studies continue throughout all phases of research to evaluate long-term safety issues. 

The standardized guidelines have been compiled to cover test methods in animal studies and in vitro studies on absorption, distribution, metabolism cind excretion in the Notification No. 496 of the PAB in 1998. The guidelines can be applicable for the drugs to be submitted after October 1999. The following principles should be considered in order to select the most appropriate methods bcised on the characteristics of test substance. It is required that the exposure data related to toxicological studies be obtained before the first human study and other pharmacokinetic data before the completion of Phcise I study in principle in accordance with the guidelines on nonclinical safety studies for conducting clinical trials (Notification No. 1019 of the PAB, 1998). 

Pharmacology/Toxicology Reviewer. Evaluates the entire body of nonclinical data and analyses, with a particular focus on the newly submitted longterm test data, to identify relevant implications for the drug s clinical safety. 

The function of clinical chemistry in toxicology (as well as in human and veterinary medicine) is to provide, via laboratory analysis, evaluations of the qualitative and quantitative characteristics of specific endogenous chemical components present in samples of blood, urine, feces, spinal fluid, and tissues. The purpose is to help identify abnormal or pathological changes in organ system functions. The most common specimens used in clinical chemistry are blood and urine, and many different tests exist to test for almost any type of chemical component in blood or urine for example, blood glucose, electrolytes, enzymes, hormones, lipids (fats), other metabolic substances, and proteins. The tests used were all initially applied to human clinical medicine, and may not possess the same utility when performed as part of nonclinical toxicity studies in a wide variety of other species. 

GLP regulates all nonclinical studies and was originally intended for toxicity testing only. The requirements of analytical measurements and methods in support of toxicological studies are included in the GLP. The QA/QC may serve as the quality assurance unit (QAU), which is responsible for monitoring each study to ensure that management facilities, equipment, personnel, methods, practice, controls, SOPs, and final reports conform to the regulation. 

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