Hsuan-Ping Chang1, Zhe Li1, Dhaval K Shah2. 1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Pharmacy Building, Buffalo, New York, 14214-8033, USA. 2. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Pharmacy Building, Buffalo, New York, 14214-8033, USA. dshah4@buffalo.edu.
Abstract
PURPOSE: To quantitate and mathematically characterize the whole-body pharmacokinetics (PK) of different ADC analytes following administration of an MMAE-conjugated ADC in tumor-bearing mice. METHODS: The PK of different ADC analytes (total antibody, total drug, unconjugated drug) was measured following administration of an MMAE-conjugated ADC in tumor-bearing mice. The PK of ADC analytes was compared with the whole-body PK of the antibody and drug obtained following administration of these molecules alone. An ADC PBPK model was developed by linking antibody PBPK model with small-molecule PBPK model, where the drug was assumed to deconjugate in DAR-dependent manner. RESULTS: Comparison of antibody biodistribution coefficient (ABC) values for total antibody suggests that conjugation of drug did not significantly affect the PK of antibody. Comparison of tissue:plasma AUC ratio (T/P) for the conjugated drug and total antibody suggests that in certain tissues (e.g., spleen) ADC may demonstrate higher deconjugation. It was observed that the tissue distribution profile of the drug can be altered following its conjugation to antibody. For example, MMAE distribution to the liver was found to increase while its distribution to the heart was found to decrease upon conjugation to antibody. MMAE exposure in the tumor was found to increase by ~20-fold following administration as conjugate (i.e., ADC). The PBPK model was able to a priori predict the PK of all three ADC analytes in plasma, tissues, and tumor reasonably well. CONCLUSIONS: The ADC PBPK model developed here serves as a platform for translational and clinical investigations of MMAE containing ADCs.
PURPOSE: To quantitate and mathematically characterize the whole-body pharmacokinetics (PK) of different ADC analytes following administration of an MMAE-conjugated ADC in tumor-bearing mice. METHODS: The PK of different ADC analytes (total antibody, total drug, unconjugated drug) was measured following administration of an MMAE-conjugated ADC in tumor-bearing mice. The PK of ADC analytes was compared with the whole-body PK of the antibody and drug obtained following administration of these molecules alone. An ADC PBPK model was developed by linking antibody PBPK model with small-molecule PBPK model, where the drug was assumed to deconjugate in DAR-dependent manner. RESULTS: Comparison of antibody biodistribution coefficient (ABC) values for total antibody suggests that conjugation of drug did not significantly affect the PK of antibody. Comparison of tissue:plasma AUC ratio (T/P) for the conjugated drug and total antibody suggests that in certain tissues (e.g., spleen) ADC may demonstrate higher deconjugation. It was observed that the tissue distribution profile of the drug can be altered following its conjugation to antibody. For example, MMAE distribution to the liver was found to increase while its distribution to the heart was found to decrease upon conjugation to antibody. MMAE exposure in the tumor was found to increase by ~20-fold following administration as conjugate (i.e., ADC). The PBPK model was able to a priori predict the PK of all three ADC analytes in plasma, tissues, and tumor reasonably well. CONCLUSIONS: The ADC PBPK model developed here serves as a platform for translational and clinical investigations of MMAE containing ADCs.
Authors: Eugenia Kraynov; Amrita V Kamath; Markus Walles; Edit Tarcsa; Antoine Deslandes; Ramaswamy A Iyer; Amita Datta-Mannan; Priya Sriraman; Michaela Bairlein; Johnny J Yang; Matthew Barfield; Guangqing Xiao; Enrique Escandon; Weirong Wang; Dan A Rock; Nagendra V Chemuturi; David J Moore Journal: Drug Metab Dispos Date: 2015-12-15 Impact factor: 3.922
Authors: Rebecca A Herbertson; Niall C Tebbutt; Fook-Thean Lee; David J MacFarlane; Bridget Chappell; Noel Micallef; Sze-Ting Lee; Timothy Saunder; Wendie Hopkins; Fiona E Smyth; David K Wyld; John Bellen; Daryl S Sonnichsen; Martin W Brechbiel; Carmel Murone; Andrew M Scott Journal: Clin Cancer Res Date: 2009-10-13 Impact factor: 12.531