Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
The 500 Dalton rule for the skin penetration of chemical compounds and drugs.
Author:
Bos JD, Meinardi MMHM
Year:
2000
Bibliographic source:
Experimental Dermatology 9; 165-169.
Reference Type:
publication
Title:
Oral Delivery of Peptide Drugs - Barriers and Developments.
Author:
Hamman JH, Enslin GM, Kotz AF
Year:
2005
Bibliographic source:
Biodrugs 2005; 19 (3): 165-177
Reference Type:
publication
Title:
Alternative routes of administration as an approach to improve insulin therapy: update on dermal, oral, nasal and pulmonary insulin therapy.
Author:
Heinemann L, Pfützner A, Heise T
Year:
2001
Bibliographic source:
Current Pharmaceutical Design 7; 1327-1351
Reference Type:
publication
Title:
Molecular, pharmacological and clinical aspects of liraglutide, a once-daily human GLP-1 analogue
Author:
Russell-Jones
Year:
2009
Bibliographic source:
Molecular and Cellular Endocrinology 297, 137–140
Reference Type:
publication
Title:
Oral peptide and protein delivery: intestinal obstacles and commercial prospects
Author:
Smart AL, Gaisford S, Basit AW
Year:
2014
Bibliographic source:
Expert Opinion on Drug Delivery 11:8, 1323-1335
Reference Type:
other company data
Title:
Unnamed
Year:
1998

Materials and methods

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on 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 enzymes released from the pancreas into the intestine (Hamman et al. 2005). For the polypeptide calcitonin (consisting of 32 amino acids and a MW of 3.4 kDa i.e. comparable to liraglutide precusor) Smart et al. (2014) reported 100% degradation during one hour in artificial intestinal fluid and after only 5 minutes in intestinal fluid from rats. For the active pharmaceutical ingredient liraglutide an oral absorption rate of 0.02% has been found in rats orally dosed in combination with a carrier expected to enhance oral absorption (Novo Nordisk 2015). Thus, oral exposure to liraglutide precusor is not expected to lead to any significant absorption due to rapid degradation in the gastrointestinal tract.

Dermal absorption: Liraglutide precusor 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). An absorption at a very low percentage of insulin (a polypeptide where dermal absorption has been intensively studied) 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). Thus, under normal conditions, systemic uptake from dermal exposure to insulin and similar proteins/ polypetides is considered to be very low / insignificant.

Inhalational absorption: Pfister et al. (2014) reviewed data on the bioavailability of selected peptides and proteins in relation to inhalation exposure. For calcitonin having a similar molecular size as liraglutide precusor an absorption rate of 11.5-17% was found after intratracheal instillation in rats. Thus, systemic absorption to a certain extent may be expected in relation to inhalational exposure to liraglutide precusor.
Details on excretion:
For human GLP-1 a half-life in blood of < 2 minutes was found as the substance is rapidly degraded by the enzyme dipeptidyl peptidase 4 (Russell-Jones 2009). The same rapid degradation can be assumed for liraglutide precusor due to the almost identical structure.

For the active pharmaceutical agent liragludtide the rapid degradation was circumvented by the attachment of palmitic acid to the precusor and a half-life in human blood of about 13 hours was obtained due to this molecular modification (Russell-Jones 2009).

Metabolite characterisation studies

Details on metabolites:
No studies regarding identification of metabolites of liraglutide and semaglutide have been conducted. As for human insulin a fast degradation of liraglutide and semaglutide into inactive fragments is expected. The amino acids from the substance is expected to take part in the general metabolic pool of the body (Novo Nordisk 1998).

Applicant's summary and conclusion

Conclusions:
For GLP-1, liraglutide and semaglutide the oral and demal absorption is considered negligible, because of degradation of the protein in the gastrointestinal tract and due to lack of dermal penetration and absorption of the large, proteinaceous molecule.

From rats experiments with calcitonin that have a similar molecular size as liraglutide precusor an absorption rate of 11.5-17% was found after intratracheal instillation. Thus, systemic absorption to a certain extent may be expected in relation to inhalational exposure to liraglutide precusor.

For human GLP-1 a half-life in blood of < 2 minutes was found as the substance is rapidly degraded by the enzyme dipeptidyl peptidase 4 (Russell-Jones 2009). The same rapid degradation can be assumed for liraglutide precusor due to the almost identical structure.

For the active pharmaceutical agent liragludtide the rapid degradation was circumvented by the attachment of palmitic acid to the precusor and a half-life in human blood of about 13 hours was obtained due to this molecular modification (Russell-Jones 2009).

No studies regarding identification of metabolites of liraglutide and semaglutideh ave been conducted. The amino acids from the substance is expected to take part in the general metabolic pool of the body.
Executive summary:

For GLP-1, liraglutide and semaglutide the oral and demal absorption is considered negligible, because of degradation of the protein in the gastrointestinal tract and due to lack of dermal penetration and absorption of the large, proteinaceous molecule.

From rats experiments with calcitonin that have a similar molecular size as liraglutide precusor an absorption rate of 11.5-17% was found after intratracheal instillation. Thus, systemic absorption to a certain extent may be expected in relation to inhalational exposure to liraglutide precusor.

For human GLP-1 a half-life in blood of < 2 minutes was found as the substance is rapidly degraded by the enzyme dipeptidyl peptidase 4 (Russell-Jones 2009). The same rapid degradation can be assumed for liraglutide precusor due to the almost identical structure.

For the active pharmaceutical agent liragludtide the rapid degradation was circumvented by the attachment of palmitic acid to the precusor and a half-life in human blood of about 13 hours was obtained due to this molecular modification (Russell-Jones 2009).

No studies regarding identification of metabolites of liraglutide and semaglutide have been conducted. The amino acids from the substance is expected to take part in the general metabolic pool of the body.