Development of a Physiologically-Based Pharmacokinetic Model for Whole-Body Disposition of MMAE Containing Antibody-Drug Conjugate in Mice

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 similar to 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.

Automated summary

This study aimed to quantitate and mathematically characterize the whole-body pharmacokinetics of different ADC analytes following administration of an MMAE-conjugated ADC. The results showed that conjugation of MMAE did not significantly affect the PK of the antibody, but ADC may demonstrate higher deconjugation in certain tissues. Additionally, the conjugation of MMAE to antibody altered its tissue distribution profile.