Severine Urdy 1, Sichen Wang 2, Nassim Djebli 3
1 PhinC Development (Massy, France), 2 Jiangsu Hengrui Pharmaceutical (Shanghai, China), 3 Luzsana Biotechnology (Basel, Switzerland)
Introduction
A quantitative understanding of the whole-body pharmacokinetics (PK) of antibody-drug conjugates (ADCs) is essential for establishing the exposure-response relationship and evaluating the safety profile of ADCs [1].
Mechanistic approaches, such as physiologically based pharmacokinetic (PBPK) models and quantitative systems pharmacology (QSP) models, integrate multiple types of data and knowledge with computational modeling to examine the relationships between the drug, the physiology of the organism and some aspects of the disease. Several preclinical, clinical or translational PBPK and QSP models have been published in recent years, especially for first-generation ADCs targeting HER2 [2-5]. In addition, a human PBPK model was published for an ADC with a new payload, Rezetecan [6]. Here, we build on these approaches to derive a mice PBPK model of an anti-HER2 ADC with Rezetecan payload [7] in the Open Systems Pharmacology Suite [8].
Objectives
• Predict and verify the whole-body PK of the different ADC analytes in tumor-bearing mice with detailed biodistribution data
• Identify the most sensitive parameters that can affect tumor exposure of the different ADC analytes
Methods
A small molecule PBPK model of Rezetecan, including liver and renal elimination, was built using rat PK data obtained from single administration of payload at three doses. Most input parameters are defined from experiments, and only renal clearance is optimized. This model is translated to mouse by allometric scaling of clearances and by updating the plasma protein binding, keeping the other small molecule parameters constant in the next steps.
A mouse bearing a tumor compartment is defined with a composition assumed to be 82-86 % cellular, 13-17 % interstitial and <1 % vascular, to represent a human cell-derived xenograft originating from a solid cancer [9].
A 3 analyte-PBPK model is built by assuming a one-step plasmatic deconjugation of administered ADC which leads to the release of naked antibody (nAb) and free payload (FP) in blood circulation according to drug-to-antibody ratio. Large molecule parameterization comes from experiments and literature estimations [2-3]. ADC and nAb differ slightly in their molecular weights according to their conjugation state.
This model is extended for target-mediated drug disposition (TMDD) [10-11] to account for target turnover, drug-target internalization and subsequent payload release into cells upon target binding in healthy and tumoral cells. The model predicts the total antibody (TAb) plasmatic concentration to facilitate comparison to bioanalysis measurements.
Results
The model was calibrated with plasma concentrations of the three analytes and payload exposure in whole tumors at two doses. The predicted exposure in healthy and tumor tissues was checked against biodistribution data in NCI-N87 xenografted mice administered at a different dose. A parameter sensitivity analysis shows that the most sensitive calibrated parameters for the plasma PK of the ADC, TAb and FP are related to the deconjugation rate and the target expression in healthy tissues. The most sensitive calibrated parameters for whole tumor payload exposure are the rates of target degradation and drug-target internalization. The model suggests that tumor intracellular payload exposure is also sensitive to tumor blood flow and composition (vascular and cellular fraction) as well as target expression. In healthy tissues, intracellular payload exposure seems highly sensitive to the rate of target degradation and variably sensitive to target expression depending on tissue.
Conclusions
The PBPK model was able to reproduce the PK of all three ADC analytes in plasma, tissues, and tumor reasonably well and will be further tested on different xenografted mice administered with the same ADC and other ADCs with the same payload. This model can serve as a platform for translational and clinical investigations of safety and efficacy of ADCs with Rezetecan payload.
References:
References
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[10] Zasedateleva, T. et al. (2024) CPT: Pharmacometrics & Systems Pharmacology, 13(12), pp. 2068–2086. https://doi.org/10.1002/psp4.13262.
[11] Cao, Y. and Jusko, W.J. (2014) Journal of Pharmacokinetics and Pharmacodynamics, 41(4), pp. 375–387. https://doi.org/10.1007/s10928-014-9372-2.
Reference: PAGE 34 (2026) Abstr 12197 [www.page-meeting.org/?abstract=12197]
Poster: Drug/Disease Modelling - Absorption & PBPK