Influence of Molecular size on the clearance of antibody fragments.
Pharm Res
; 34(10): 2131-2141, 2017 Oct.
Article
in En
| MEDLINE
| ID: mdl-28681164
ABSTRACT
PURPOSE:
To establish a continuous relationship between the size of various antibody fragments and their systemic clearance (CL) in mice.METHODS:
Two different orthogonal approaches have been used to establish the relationship. First approach uses CL values estimated by non-compartmental analysis (NCA) to establish a correlation with protein size. The second approach simultaneously characterizes the PK data for all the proteins using a 2-compartment model to establish a relationship between protein size and pharmacokinetic (PK) parameters.RESULTS:
Simple mathematical functions (e.g. sigmoidal, power law) were able to characterize the CL vs. protein size relationship generated using the investigated proteins. The relationship established in mouse was used to predict rat, rabbit, monkey, and human relationships using allometric scaling. The predicted relationships were found to capture the available spares data from each species reasonably well.CONCLUSIONS:
The CL vs. protein size relationship is important for establishing a robust quantitative structure-PK relationship (QSPKR) for protein therapeutics. The relationship presented here can help in a priori predicting plasma exposure of therapeutic proteins, and together with our previously established relationship between plasma and tissue concentrations of proteins, it can predict the tissue exposure of non-binding proteins simply based on molecular weight/radius and dose.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Immunoglobulin Fragments
/
Models, Biological
/
Antibodies, Monoclonal
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Pharm Res
Year:
2017
Document type:
Article
Affiliation country:
United States