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Across-Species Scaling of Monoclonal Antibody Pharmacokinetics Using a Minimal PBPK Model

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ABSTRACT

Purpose

To examine the across-species scalability of monoclonal antibody (mAb) pharmacokinetics (PK) and assess similarities in tissue distribution across species using a recently developed minimal PBPK (mPBPK) model.

Methods

Twelve sets of antibody PK data from various species were obtained from the literature, which were jointly and individually analyzed. In joint analysis, vascular reflection coefficients for tissues with either tight (σ 1 ) or leaky endothelium (σ 2 ) were assumed consistent across species with systemic clearance allometrically scaled (CL = a∙BW b). Four parameters (σ 1 , σ 2 , a, and b) were estimated in the joint analysis. In addition, the PK from each species was individually analyzed to assess species similarities in tissue distribution.

Results

Twelve mAb PK profiles were well-captured by the mPBPK model in the joint analysis. The estimated σ 1 ranged 0.690 to 0.999 with an average of 0.908; and σ 2 ranged 0.258 to 0.841 with an average of 0.579. Clearance was reasonably scaled and b ranged 0.695 to 1.27 averaging 0.91. Predictions of plasma concentrations for erlizumab and canakinumab in humans using parameters obtained from fitting animal data were consistent with actual measurements.

Conclusions

Therapeutic mAbs given IV usually exhibit biexponential kinetics with their distribution properties best captured using physiological concepts. The mPBPK modeling approach may facilitate efforts in translating antibody distribution and overall PK across species.

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Abbreviations

AIC:

Akaike Information Criterion

AUC:

Area under the plasma concentration-time curve

BW:

Body weight

CV:

Coefficient of variation

FIH:

First-in-human

ISF:

Interstitial fluid

L:

Lymph flow

mAb:

Monoclonal antibody

mPBPK:

Minimal physiologically based pharmacokinetic modeling

NCA:

Non-compartmental analysis

PBPK:

Physiologically based pharmacokinetic modeling

PK:

Pharmacokinetic

SC:

Schwarz Criterion

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ACKNOWLEDGMENTS AND DISCLOSURES

This research was supported by the National Institutes of Health Grant GM57980 and the UB Center for Protein Therapeutics.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, 14214, USA

    Jie Zhao, Yanguang Cao & William J. Jusko

Authors
  1. Jie Zhao
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  2. Yanguang Cao
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  3. William J. Jusko
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Corresponding author

Correspondence to William J. Jusko.

Electronic supplementary material

Also provided are further references pertaining to the specific antibodies that were modeled and the Adapt computer code used for joint modeling of mAb profiles from two or more species.

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Zhao, J., Cao, Y. & Jusko, W.J. Across-Species Scaling of Monoclonal Antibody Pharmacokinetics Using a Minimal PBPK Model. Pharm Res 32, 3269–3281 (2015). https://doi.org/10.1007/s11095-015-1703-5

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  • DOI: https://doi.org/10.1007/s11095-015-1703-5

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