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Second-generation minimal physiologically-based pharmacokinetic model for monoclonal antibodies

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Abstract

Minimal physiologically-based pharmacokinetic (mPBPK) models provide a sensible modeling approach when fitting only plasma (or blood) data yielding physiologically-relevant PK parameters that may provide more practical value than parameters of mammillary models. We propose a second-generation mPBPK model specifically for monoclonal antibodies (mAb) by including (lumping) several essential components of mAb PK used in full PBPK models. These components include convection as the primary mechanism of antibody movement from plasma into tissues and return to plasma with interstitial fluid as the major extravascular distribution space. The model divides tissue spaces into two groups according to their vascular endothelial structure, leaky and tight, which consequently allows discernment of two types and general sites of distribution. This mPBPK model was applied to two mAbs in mice and ten mAbs with linear kinetics in humans. The model captured their plasma PK profiles well with predictions of concentrations in interstitial fluid for two types of tissues. Predictions of tissue concentrations for mAb 7E3 and 8C2 were consistent with actual measurements in mice, indicating the feasibility of this model in assessing extravascular distribution in the two categories of tissues. The vascular reflection coefficients (σ 1) of tight tissues (V tight ) ranged 0.883–0.987 and coefficients (σ 2) for leaky tissues (V leaky ) ranged 0.311 to 0.837. The plasma clearance (CL p ) varied among the mAbs in humans from 0.0054 to 0.03 L/h. In addition, applying this model generates parameters for mAb transcapillary escape rates and assesses major sites of elimination. Four of ten mAbs exhibited better fitting statistics premised on elimination from interstitial fluid than from plasma. This approach allows comparisons of mAb PK when only plasma data are available, provides more realistic parameters and predictions than mammillary models, and may provide an intermediate step towards utilizing full PBPK models for mAbs.

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Acknowledgments

The authors acknowledge Drs. Lubna Abuqayyas and Amit Garg for kindly sharing the original datasets of mAb 7E3 and 8C2. This research was supported by the National Institutes of Health Grant GM57980, the University at Buffalo—Pfizer Strategic Alliance, and the UB Center for Protein Therapeutics.

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  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 404 Kapoor Hall, Buffalo, NY, 14214-8033, USA

    Yanguang Cao, Joseph P. Balthasar & William J. Jusko

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  1. Yanguang Cao
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  2. Joseph P. Balthasar
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Correspondence to William J. Jusko.

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The supplementary file provides the Adapt 5 and the Phoenix software code for application of the mPBPK model for data from human subjects.

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Cao, Y., Balthasar, J.P. & Jusko, W.J. Second-generation minimal physiologically-based pharmacokinetic model for monoclonal antibodies. J Pharmacokinet Pharmacodyn 40, 597–607 (2013). https://doi.org/10.1007/s10928-013-9332-2

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