Chang Hsuan-Ping, Shah Dhaval K
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Pharmacy Building, Buffalo, NY, 14214-8033, USA.
J Pharmacokinet Pharmacodyn. 2025 May 5;52(3):27. doi: 10.1007/s10928-025-09978-3.
The objective of this work was to develop a translational physiologically-based pharmacokinetic (PBPK) model for antibody-drug conjugates (ADCs), using monomethyl auristatin E (MMAE)-based ADCs. A previously established dual-structured whole-body PBPK model for MMAE-based ADCs in mice was scaled to higher species (i.e., rats and monkeys) and humans. Species-specific physiological and drug-related parameters for the payload and antibody backbone of ADCs were obtained from literature. Parameters associated with payload release, including the deconjugation rate, were optimized using an allometric scaling approach, and antibody degradation rate was adjusted to account for the enhanced clearance of ADCs due to conjugation across different species. The translational PBPK model predicted the PK profiles for various ADC analytes in rats, monkeys, and humans reasonably well. The optimized PBPK model suggested decreased rate of deconjugation for ADCs in higher species, whereas the effects of payload conjugation on ADC clearance were more pronounced in higher species and humans. The translational PBPK model presented here may enable prediction of different ADC analyte PK at the site-of-action, offering valuable insights for the development of exposure-response relationships for ADCs. The modeling framework presented here can also serve as a platform for the development of PBPK model for other ADCs.
本研究的目的是使用基于单甲基奥瑞他汀E（MMAE）的抗体药物偶联物（ADC）开发一种转化的基于生理的药代动力学（PBPK）模型。将先前建立的小鼠中基于MMAE的ADC的双结构全身PBPK模型扩展到更高等物种（即大鼠和猴子）以及人类。从文献中获取了ADC的有效载荷和抗体骨架的物种特异性生理和药物相关参数。使用异速生长比例法优化了与有效载荷释放相关的参数，包括去共轭率，并调整了抗体降解率，以考虑不同物种间共轭导致的ADC清除率增加。转化的PBPK模型较好地预测了大鼠、猴子和人类中各种ADC分析物的药代动力学特征。优化后的PBPK模型表明，高等物种中ADC的去共轭率降低，而有效载荷共轭对ADC清除率的影响在高等物种和人类中更为显著。本文提出的转化PBPK模型可以预测作用部位不同ADC分析物的药代动力学，为ADC暴露-反应关系的发展提供有价值的见解。本文提出的建模框架还可以作为开发其他ADC的PBPK模型的平台。
