A Whole body Physiologically based Pharmacokinetic Model for Antibody drug conjugates - model development and validation in rat
Linzhong Li(1), Shang-Chiung Chen(2), Felix Stader(1), Rachel Rose(1), Indranil Rao(1), Iain Gardner(1), Masoud Jamei(1), Ben-Quan Shen(2), Victor Yip(2), Yuan Chen(2), Jin Yan Jin(2), Chunze Li(2)
(1) Simcyp (A Certara Company), Blades Enterprise Centre, Sheffield, UK (2) Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
Objectives: To develop and qualify a whole body physiologically-based Pharmacokinetic model for simulating Antibody Drug Conjugates (ADCs) disposition in tissues.
Methods: The whole body PBPK approach adapted here combines features of a previously published minimal PBPK model for mAbs [1] and a compartmental model for ADCs [2]. The base model incorporates new tissue-specific data related to IgG transport via both convection/diffusion and an FcRn-mediated pathway, including tissue-dependent FcRn expression (derived from data in transgenic mice [3]), an estimate of tissue endosomal volume, published tissue lymphatic flows, predicted vascular reflection coefficients [4], and tissue-dependent recycling rates [5]. This base model is applied to all ADC DAR (Drug Antibody Ratio) species, which are subject to deconjugation, catabolism, and any other additional clearance, resulting in release of the payload. The released fluxes of payload are directly fed into a full PBPK model describing the disposition of the small molecule drug which is treated as a metabolite of the ADC. Target binding models to account for target mediated disposition (TMDD) can be applied to any possible combination of multiple target binding in plasma and the interstitial space of any tissue. The ADC model parameterised with DAR-dependency allows simulation studies on various factors which influence ADC disposition to be conducted. Model verification was performed using in vivo rat data to qualify the model in three steps: (1) matching IgG plasma and tissue profiles in rat, (2) matching the plasma profile of naked monoclonal antibody (mAb) for a vc-MMAE ADC, (3) matching plasma and tissue profiles of the vc-MMAE ADC.
Results: The base model adequately describes IgG kinetics in rat, and the plasma profile of naked mAb for vc-MMAE ADC is matched well when the in vitro binding affinity of human IgG to rat FcRn is accounted for [6]. The profiles of conjugated payload and released payload in both plasma and individual tissues can be matched well by specifying DAR-dependent plasma clearances and delayed release of payload from the ADC.
Conclusions: The developed full PBPK model for ADCs provides a useful platform to study the integrated effect of different processes on ADC disposition. The model was successful in predicting the in vivo ADC disposition in rat using available physiological and in vitro data together with a fundamental understanding of the mechanisms of ADC disposition.
References:
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