Single-dose toxicity

The single-dose toxicity studies were performed in two mammalian species, rat and mouse, by the route used in clinical practice, that is oral, as well as that ensuring adequate systemic exposure to the drug, that is intravenous. The subacute (3 months) toxicity studies were correctly carried out in the two animal species (rat, dog) in which also the pharmacokinetics was studied. Since in accordance with the International Conference on Harmonization (CPMP/ICH/286/95), 3-month toxicity studies support clinical trials for up to 1 month s duration (the longest duration of drug administration in clinical use), chronic toxicity studies have not been performed. 

In the United States, as an alternative to 2-week studies, single dose toxicity studies with extended examinations can support single dose human trials. 

Single-dose toxicity studies fall into two categories preliminary and definitive studies. Preliminary studies are performed to provide an estimate of the maximum nonlethal dosage (MNLD) for use in definitive studies. Definitive studies are performed to evaluate effects that may result from acute exposure to the MNLD and predict effects of overdosage in man. 

PYA copolymer Bioavailability enhancer Single-dose toxicity (in rat and dog) and maximum tolerated dose/short-term (2wks—oral) (in rat and dog) toxicity as well as 2 in vitro and 1 in vivo genotoxicity studies. ADME studies with 14C-labelled material are underway and a 3-6 mo toxicity study in the rat is planned No adverse effects seen to date 41... 

Zinc absorption is inhibited by most food and the elevated plasma level lasts only 5 h after a dose thus it is better given five or six times a day, 1 h before or after meals. Zinc acetate may be better tolerated than the sulfate salt. Brewer prefers 25 mg elemental zinc, administered as the acetate, five or six times a day.53 Zinc is relatively non-toxic as a drug. If more than 1 g zinc is ingested in a single dose, toxic symptoms such as abdominal pain, nausea, vomiting, fever, drowsiness and lethargy may occur. A more significant toxicity problem is zinc-induced copper deficiency which can be corrected with a supplement of 0.5 mg of copper as copper sulfate per day.53... 

In the US, single dose toxicity studies with extended examinations can support single-dose human trials. This concept encouraged the EU to offer comparable options with the Microdosing concept. This principle may be especially valuable for gaining early data for Go/No go decisions, when several candidates are being developed in parallel. 

Single-Dose Toxicity (in order by species, by route)... 

In the EU and the USA, two week studies are the minimum duration. In Japan, 2 week non-rodent and 4 week non-rodent studies are needed. In the USA, as an alternative to 2-week studies, single dose toxicity studies with extended examinations (hematology, clinical chemistry, urinalysis, macroscopic and microscopic pathology) can support single dose human trials. 

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