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Development of a Translational Physiologically Based Pharmacokinetic Model for Antibody-Drug Conjugates: a Case Study with T-DM1

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  • Theme: Systems Pharmacokinetics Models for Antibody-Drug Conjugates
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ABSTRACT

Systems pharmacokinetic (PK) models that can characterize and predict whole body disposition of antibody-drug conjugates (ADCs) are needed to support (i) development of reliable exposure-response relationships for ADCs and (ii) selection of ADC targets with optimal tumor and tissue expression profiles. Towards this goal, we have developed a translational physiologically based PK (PBPK) model for ADCs, using T-DM1 as a tool compound. The preclinical PBPK model was developed using rat data. Biodistribution of DM1 in rats was used to develop the small molecule PBPK model, and the PK of conjugated trastuzumab (i.e., T-DM1) in rats was characterized using platform PBPK model for antibody. Both the PBPK models were combined via degradation and deconjugation processes. The degradation of conjugated antibody was assumed to be similar to a normal antibody, and the deconjugation of DM1 from T-DM1 in rats was estimated using plasma PK data. The rat PBPK model was translated to humans to predict clinical PK of T-DM1. The translation involved the use of human antibody PBPK model to characterize the PK of conjugated trastuzumab, use of allometric scaling to predict human clearance of DM1 catabolites, and use of monkey PK data to predict deconjugation of DM1 in the clinic. PBPK model-predicted clinical PK profiles were compared with clinically observed data. The PK of total trastuzumab and T-DM1 were predicted reasonably well, and slight systemic deviations were observed for the PK of DM1-containing catabolites. The ADC PBPK model presented here can serve as a platform to develop models for other ADCs.

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ACKNOWLEDGEMENTS

This work was supported by the NIH grant GM114179 to D.K.S and the Centre for Protein Therapeutics Consortium at the University at Buffalo. A.K. is a recipient of John Kapoor Fellowship in Pharmaceutical Sciences. We would like to thank Dr. Mark Penney for his valuable suggestions during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Kapoor Hall, Buffalo, NY, 14214, USA

    Antari Khot & Dhaval K. Shah

  2. UCB Pharma, 216 Bath Rd, Slough, SL1 3WE, UK

    Jay Tibbitts

  3. Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, CA, 91320, USA

    Dan Rock

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  1. Antari Khot
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Correspondence to Dhaval K. Shah.

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Communicated by: Dhaval K. Shah

ELECTRONIC SUPPLEMENTARY MATERIAL

Supplementary Figure 1

(A) The modified 2-compartmental model used to estimate ADC deconjugation rate. (B) Model fitting to rat data for estimation of DM1 deconjugation rate. (C) Model fitting to monkey data for estimation of DM1 deconjugation rate. (GIF 24 kb)

High-resolution image (TIFF 59 kb)

Supplementary Figure 2

Translated T-DM1 PBPK model-predicted plasma, tissue, and tumor concentrations of T-DM1, unconjugated DM1, and total DM1 in humans. (GIF 65 kb)

High-resolution image (TIFF 175 kb)

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Khot, A., Tibbitts, J., Rock, D. et al. Development of a Translational Physiologically Based Pharmacokinetic Model for Antibody-Drug Conjugates: a Case Study with T-DM1. AAPS J 19, 1715–1734 (2017). https://doi.org/10.1208/s12248-017-0131-3

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