Testing preclinical

The objective of the preclinical phase is to assure that new substances are safe for humans before they are tested in patients. The tasks of the preclinical phase are summarized in Table 10.6. 

a few kilograms of the test substance must be ssmthesized to have enough material for further testing. The purity and the impurities are determined by spectroscopic and chromatographic techniques and basic 

Route of synthesis Development of an industrial synthesis method 

Properties and stability Identification of impurities, physicochemical properties, stability upon storage 

Toxicity Acute toxicity in rats and mice (single-dose appUcation), 4 weeks to 2 years repeated dose toxicity in rats and dogs Genetic toxicity in vitro and in vivo, for example, mutagenicity Reproductive toxicity in rats and rabbits 

---

Barr AM, Kinney JW, Hill MN et al (2006) A novel, systemically active, selective galanin receptor type-3 ligand exhibits antidepressant-like activity in preclinical tests. Neurosci Lett 405 111-115... 

After completing preclinical testing, a company files an Investigational New Drug (IND) application with the regulators (the FDA in the U.S.), so that clinical studies in man can begin. The IND shows results of all experiments to this point, a detailed proposal for the clinical study, the expected mode of action for the drug, and any side effects observed. All clinical trials will also be reviewed and approved by the Institutional Review Board (IRB) at the clinic where the trials will be run. 

In addition, tests for mutagenicity and carcinogenicity are not likely required for most biopharma-ceutical substances. The regulatory guidelines and industrial practices relating to biopharmaceuti-cal preclinical trials thus remain in an evolutionary mode, and each product is taken on a case-by-case basis. An overview of the main preclinical tests undertaken for a sample biopharmaceutical... 

Other compounds, such as ZK-703 and ZK-253, are currently under preclinical testing, and preliminary data show a pure antiestrogen activity in xenograft breast cancer models (Hoffmann et al. 2004). 

Bala, S., Weaver, J., and Hastings, K.L., Clinical relevance of preclinical testing for allergic side effects, Toxicology, 209, 195, 2005. 

The number of species necessary in preclinical testing programs varies. However, there is no specific requirement for the routine use of two species (e.g., one rodent and one nonrodent) in toxicology studies of biological products. 

It is the intent of this chapter to provide an understanding of these adverse immunological effects, the types of preclinical tests that may be used to detect them, and approaches for testing and interpreting test results. 

IND Investigational New Drug application, filed with FDA after preclinical testing is complete asking for permission to proceed with human tests. 

Compound. A chemical synthesized or prepared from natural sources that is evaluated for its biological activities in preclinical tests. 

All stages involving the evaluation and formulation of a new medicine (after the medicine has been discovered and has gone through preclinical testing), until it reaches the market. 

Caponigro G, Sellers WR. Advances in the preclinical testing of cancer therapeutic hypotheses. Nat Rev Drug Discov. Mar 10(3) 179-87. 

The company tiles an IND with the U.S. Food and Drug Administration (FDA) seeking permission to test compound in humans, and describing results ot preclinical tests. The IND automatically becomes effective unless the FDA rejects it within 30 days. 

Currently the only specific pharmacological therapeutic option available for AD patients is treatment with cholinesterase inhibitors, which provide moderate benefits in a subset of patients for a limited period [7]. More efficient future therapeutic strategies may be directed at the metabolic events resulting in Ap accumulation, for example by inhibition of P- or y-sec-retase [7], or at the prevention of neuronal loss by neurotrophin therapy [6]. The availability of transgenic mouse models of the disease, such as mice overexpressing APP mutants [8], and the utilization of primate models of cerebral amyloid [9] permits preclinical testing of novel diagnostic and therapeutic approaches. 

Scales MDC. Relevance of preclinical testing to risk assessment. BIRA J 1990 9 11-14. 

After adequate preclinical testing has been completed, an IND must be submitted to FDA to justify clinical investigation in humans. The content and format of an IND are set out in detail... 

---