Preclinical trials distribution

Preclinical trials stage II Pharmacokinetics (absorption, distribution, metabolism, and excretion), subchronic toxicity, teratogenicity, mutagenicity, scale-up of synthesis, development of final dosage form, and production of clinical samples [Chemistry, Manufacturing, and Control (CMC) section for FDA],... 

Despite encouraging preclinical results with Group I agonists, clinical data remain lacking. Further, group I receptors have a markedly different cellular distribution in primates than rodents (Muly et al., 2003 Paquet and Smith, 2003). Primate studies and eventual clinical trials therefore will be needed to validate this target for the treatment of neuropsychiatric disorders. Nevertheless, the preclinical efficacy of these compounds remains encouraging for eventual therapeutic utility. 

The absorption, distribution, metabolism, and excretion in the species used in the toxicology trials should be discussed. Quantitative or notable qualitative differences in ADME between the various animal species and humans should be discussed, as well as any references to observed species differences in toxicity and extrapolation of the findings to humans. The significance of these findings to the interpretation of the results of the carcinogenicity, bioassay, and other preclinical toxicity trials should be considered. 

Of the cases in the VIP trial, the visual loss was attributed to the development of extensive subretinal fluid with choroidal hypofluorescence in one case and sub-retinal pigment epithelial hemorrhage in three cases. No obvious cause was detected in six cases. Vision recovered to < 20 letters lost in five of the 10 patients at three months after the events. Although preclinical studies demonstrated some damage to the RPE with PDT, the Phase III data did not suggest any increase in RPE atrophy in verte-porfin-treated patients. For both groups in the TAP study, the distribution of lesion sizes with the inclusion of surrounding atrophy did not differ from the distribution of lesion sizes without atrophy. 

A DNA vaccine candidate that has successfully passed all preclinical hurdles needs to be tested clinically by a three-phased scheme as outlined in Chapter 4. As defined by a European Council directive, a clinical trial means ... any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of. .. investigational medicinal product(s), and/or to identify any adverse reactions. .. and/or to study absorption, distribution. 

---