Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

Description of key information

Absorption

Oral absorption:In the gastrointestinal tract proteins and polypeptides are broken down into a mixture of subunits that are sufficiently small for absorption (i.e. amino acids, di-and tripeptides). Degradation of peptides within the lumen of the gastrointestinal tract may be due to instability in an acidic environment, metabolism by digestive enzymes or luminal microorganisms. Proteolysis starts in the stomach in the presence of pepsin and continues throughout the intestine. Luminal degradation of peptides is caused by exposure to enzymes released from the pancreas into the intestine (Hamman et al. 2005). Insulin is completely inactivated within 3 minutes in gastric fluids from pigs, and in rats less than 1% of insulin was found to be absorbed after oral administration (Smart et al. 2014). The major problem for therapeutic oral insulin administration, besides proteolysis in the stomach and the small intestine, is that there are no selective insulin transport mechanisms across the gut wall and the epithelial cells of the intestinal tract normally do not transport macromolecules. Therefore, even if insulin is dosed directly into the gut, extremely high doses are required to achieve at least some measurable insulin absorption (Heinemann et al 2001).

Thus, due to the structural similarities, the oral absorption of insulin desB30 and the read-across source substances may be considered to be minute, which is expected very much to reduce any toxic potential from oral exposure. The low degree of oral absorption may further be supported by the lack of adverse effects noted in acute oral toxicity testing of S2 and S3.

Dermal absorption: Insulin desB30 and the read-across source substances are large proteinaceous molecule and absorption through the skin is expected to be low. Skin is generally considered as a very effective barrier for larger molecules such as polypeptides and proteins. For smaller molecules it has been shown that dermal penetration and absorption has a steep decline when the molecular size of a chemical exceeds 500 Dalton (Bos et al., 2000; Heinemann et al., 2001). Some absorption at a very low percentage of insulin has been observed in hairless mice when applying an electrical potential across the skin (iontophoresis) with the aim of promoting the skin penetration (Heinemann et al. 2001). However, under normal conditions, systemic uptake from dermal exposure to insulin and similar proteins at a molecular size of about 6000 Dalton is considered to be very low / insignificant. The low degree of dermal absorption may further be supported by the lack of adverse effects noted in acute dermal oral toxicity testing of S2.

Inhalational absorption:Heinemann et al.(2005) reviewed data on the relative biopotency of insulin from the inhalational exposure route(examined as a potential new administration route in insulin therapy) compared to traditional subcutaneous administration. Overall, it was concluded that when using optimal conditions for pulmonary uptake a relative potency of about 10% could achieved from inhalational exposure. Thus, this optimal absorption rate may be considered as a valid assumption in relation to both insulin desB30 and the read-across source substances.

Metabolism/elimination

Half-life for human insulin in blood has been determined to 22 minutes in rats and 76 minutes in humans (Novo Nordisk 2001). Degradation is expected to take place by the normal pathway for peptides and amino acids in the body – however, no specific data exist.

Endogenous production

The endogenous insulin production rate (IPR) in normoglycaemic adult individuals is approximately 1.0 mg/day (or 29IU/d) with a production of1.6 IU/h from 6:00 a.m. to 8:00 p.m. and 0.8 IU/h from 8:00 p.m. to 6:00 a.m. (Novo Nordisk 2016)

Insulin Receptor binding

Human insulin receptor affinity of Insulin Human Methyl Ester relative to the API, human insulin, was found to be 108%, thus the same pharmacological mode of action as for human insulin is to be expected.

Key value for chemical safety assessment

Absorption rate - oral (%):
0
Absorption rate - dermal (%):
0
Absorption rate - inhalation (%):
10

Additional information