Journal
PHARMACEUTICAL RESEARCH
Volume 34, Issue 10, Pages 2131-2141Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-017-2219-y
Keywords
Antibody Fragments; Compartmental Modeling; Monoclonal Antibody (mAb); QSPKR; Systemic Clearance
Funding
- NIH [GM114179]
- Center for Protein Therapeutics at the University at Buffalo
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To establish a continuous relationship between the size of various antibody fragments and their systemic clearance (CL) in mice. 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. 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. 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.
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