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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015

Materials and methods

Objective of study:
other: receptor binding
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Insulin Human Methyl Ester
EC Number:
944-551-3
Molecular formula:
C258H385N65O77S6
IUPAC Name:
Insulin Human Methyl Ester
Test material form:
solid: particulate/powder

Results and discussion

Preliminary studies:
From insulin receptor binding assays (Novo Nordisk 2015) the following relative binding was observed for insulin APIs and the various insulin intermediates:    
                    
Human insulin (API, two chains):               100 %                                                                                                                                                                                             
Human insulin methyl ester (two chains):    108 %                                                                                                                                                                                                
DesB 30 human insulin (two chains) :   133 %                                                                                                                                                                  

X14DesB30 (S3, two chains):  not examined                                                                                                                                                                           

Insulin aspart (API, S1, two chains):     100% %                                                                                                                                                                                                                  
Insulin aspart ethyl ester (two chains):     103%                                                                                                                                                                                                                                                                                                                                                    
Insulin aspart precursor (T, one chain) :   0.03 %                                                                                                                                                                                               
MI3 (S2, one chain):   0.22%                                                                                                                                                                                                                                                                                                                                                                                                                                                 
These data indicate that receptor binding affinity is lost when the two amino acids chains are linked together in one chain,
most probably due to a great change in the steric form of the molecule.
As can be seen Human insulin methyl ester binds with an afinity of 108 % i.e. a comparble binding as human insulin    

Any other information on results incl. tables

From insulin receptor binding assays (Novo Nordisk 2015) the following relative binding was observed for insulin APIs and the various insulin intermediates:                        

Human insulin (API, two chains):               100 %                                                                                                                                                                                             

Human insulin methyl ester (two chains):    108 %                                                                                                                                                                                                

DesB 30 human insulin (two chains) :        133 %                                                                                                                                                                  

X14DesB30 (S3, two chains):                   not examined                                                                                                                                                                           

Insulin aspart (API, S1, two chains):          100 %                                                                                                                                                                                                                  

Insulin aspart ethyl ester (two chains):      103%                                                                                                                                                                                                                                                                                                                                                    

Insulin aspart precursor (T, one chain) :   0.03 %                                                                                                                                                                                               

MI3 (S2, one chain):   0.22%                                                                                                                                                                                                                                                                                                                                                                                                                                                 

These data indicate that receptor binding affinity is lost when the two amino acids chains are linked together in one chain,

most probably due to a great change in the steric form of the molecule.

As can be seen Human insulin methyl ester binds with an afinity of 108 % i.e. a comparble binding as human insulin   

Applicant's summary and conclusion

Conclusions:
Human insulin receptor affinity of Insulin Human Methyl Ester relative to the API, human insulin, was found to be 108% [116 to 153]. Results are given as weighted means of three independent experiments with the corresponding 95% confidence intervals.
Executive summary:

Human insulin receptor affinity of Insulin Human Methyl Ester relative to the API, human insulin, was found to be 108% [116 to 153]. Results are given as weighted means of three independent experiments with the corresponding 95% confidence intervals.

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