Application of translational physiologically based pharmacokinetic (PBPK) model for elucidating the complex disposition of ADCs: a case study with T-DM1
Cong Liu (1), Felix Stader (1), Abdallah Derbalah (1), Armin Sepp (1)
(1) Certara UK Limited, Simcyp Division
Objectives: Antibody drug conjugates (ADCs) are a class of targeted cancer therapies which aim to widen the therapeutic index by combining the specificity of monoclonal antibodies (mAbs) with the potency of covalently attached highly cytotoxic payload (warhead) compounds. ADCs are heterogeneous mixtures of molecular entities defined in terms of drug-antibody ratio (DAR) where the latter can affect its tissue distribution and pharmacokinetics (PK). The PK of ADCs is complex and involves several processes, from systemic distribution to target-mediated (as well as non-specific) cellular uptake leading to followed by FcRn-mediated recycling, lysosomal degradation and payload drug release upon which the latter can act locally or diffuse and also affect bystander cells and tissues, . The objective of this study is to (1) illustrate the workflow of development of translational PBPK model for ADCs from cynomolgus monkey to human, (2) take T-DM1 (Trastuzumab emtansine) as a case study to characterize PKs of different large molecule analytes, T-DM1 (conjugated trastuzumab) and total trastuzumab (T-DM1 + unconjugated trastuzumab).
Methods: Whole-body PBPK model of ADCs was developed in Simcyp simulator V22. Individual ADC species were described using whole-body PBPK for mAbs where different DAR-value ADC species were linked by non-specific deconjugation reactions. In the case of T-DM1, the PBPK model of unconjugated trastuzumab was developed in monkeys as the first step. Binding affinity of trastuzumab to cyFcRn (cynomolgus monkey FcRn) was optimized first to describe the PK of trastuzumab in monkeys [1]. The other model parameters were set as the default values of cynomolgus monkey endogenous IgG as implemented in Simcyp simulator. Trastuzumab is cross-reactive with cynomolgus monkey HER2 and the baseline parameters were optimised at high dose levels where HER2 can be expected to be saturated (i.e. 25mg/kg with trastuzumab or 30mg/kg with T-DM1 in monkey). In these conditions TMDD (target mediated drug disposition) model of trastuzumab in monkeys is not accounted for as the elimination phase of the drug plasma concentration follows first-order kinetics where the contribution of non-linear clearance due to TMDD is negligible.. Secondly, the trastuzumab PBPK model was extended to T-DM1 by adding the deconjugation reactions between conjugated species. These were modelled as transit compartments connected by assumed first-order rate constants. Deconjugation rates were estimated from the in vitro plasma stability study [2]. Thirdly. when scaled to human, given the clinically relevant dose of trastuzumab (initial dose 8mg/kg with subsequent 6mg/kg q3w) and T-DM1 (3.6mg/kg), clearance of trastuzumab involves both linear lysosomal catabolism and non-linear TMDD, with the latter dominating at lower drug concentration levels. The monkey PBPK model of T-DM1 was directly translated to human PBPK model with Simcyp default parameter values based on human endogenous IgG, except binding affinity to human FcRn, which was calibrated against the optimized FcRn Kd in cynomolgus monkey. A full TMDD model was activated in lung, muscle and skin that were with medium score of protein expression [3]. Parameters involved in TMDD model, including binding and dissociate rate, internalization rate of drug-target complex and degradation rate of HER2 were obtained from literature [4-6]. Abundance of HER2 was estimated by parameter estimation against clinical data from Tokuda et al. 1999 [7].
Results: The predicted plasma profiles of trastuzumab were consistent with the observed data of trastuzumab at 6mg/kg [8] and 8mg/kg in human [9]. Following i.v. injection of T-DM1, terminal half-lives of total trastuzumab and T-DM1 were 11.3 and 4.8 day in monkeys at 30mg/kg, and 5.1 and 3.1 day in human at 3.6mg/kg. The plasma profiles of T-DM1 were also well captured with multiple dosing in monkeys and human.
Conclusions: The present study demonstrates the strategy of developing translational PBPK model of ADCs with integration of in vitro, preclinical, and clinical data. With the validated large molecule model, the free payload generated as a metabolite from conjugated mAbs can be subsequently handled by whole body PBPK model within Simcyp simulator, allowing for investigations of PKs of payload and potential DDI.
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