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Influence of Molecular size on the clearance of antibody fragments

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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.

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Abbreviations

BC:

Biodistribution Coefficient

CL:

Systemic clearance

MW:

Molecular weight

NCA:

Non-compartmental analysis

PK:

Pharmacokinetics

QSPKR:

Quantitative structure-PK relationship

TMDD:

Target Mediated Drug Disposition

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Correspondence to Dhaval K. Shah.

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Li, Z., Krippendorff, BF. & Shah, D.K. Influence of Molecular size on the clearance of antibody fragments. Pharm Res 34, 2131–2141 (2017). https://doi.org/10.1007/s11095-017-2219-y

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  • DOI: https://doi.org/10.1007/s11095-017-2219-y

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