Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE).

Hsuan Ping Chang,Dhaval K Shah,Yuen Kiu Cheung

doi:10.3390/jcm10061332

Abstract

Monomethyl auristatin E (MMAE) is one of the most commonly used payloads for developing antibody–drug conjugates (ADC). However, limited studies have comprehensively evaluated the whole-body disposition of MMAE. Consequently, here, we have investigated the whole-body pharmacokinetics (PK) of MMAE in tumor-bearing mice. We show that while MMAE is rapidly eliminated from the plasma, it shows prolonged and extensive distribution in tissues, blood cells, and tumor. Highly perfused tissues (e.g., lung, kidney, heart, liver, and spleen) demonstrated tissue-to-plasma area under the concentration curve (AUC) ratios > 20, and poorly perfused tissues (e.g., fat, pancreas, skin, bone, and muscle) had ratios from 1.3 to 2.4. MMAE distribution was limited in the brain, and tumor had 8-fold higher exposure than plasma. A physiological-based pharmacokinetic (PBPK) model was developed to characterize the whole-body PK of MMAE, which accounted for perfusion/permeability-limited transfer of drug in the tissue, blood cell distribution of the drug, tissue/tumor retention of the drug, and plasma protein binding. The model was able to characterize the PK of MMAE in plasma, tissues, and tumor simultaneously, and model parameters were estimated with good precision. The MMAE PBPK model presented here can facilitate the development of a platform PBPK model for MMAE containing ADCs and help with their preclinical-to-clinical translation and clinical dose optimization.

Highlights

Antibody–drug conjugates (ADCs) have become a promising class of drug molecules for the treatment of cancer
Noncompartmental analysis (NCA) showed that the plasma area under the concentration curve (AUC) of Monomethyl auristatin E (MMAE) from 0 to 12 h was 54.3 ng·h/mL, and the AUC from 0 to infinite was 54.5 ng·h/mL, which indicates that the majority of the systemic exposure of MMAE was limited to 12 h
We observed that while MMAE is rapidly eliminated from the systemic circulation, it shows prolonged retention in tissues, tumor, and blood cells

Summary

Introduction

Antibody–drug conjugates (ADCs) have become a promising class of drug molecules for the treatment of cancer. There have been nine ADCs approved by the United States. Food and Drug Administration (FDA), and more than 80 ADCs are in clinical trials [1]. Monomethyl auristatin E (MMAE) is one of the most commonly used payloads to make. ADCs, and Adcetris® (brentuximab vedotin), Padcev® (enfortumab vedotin-ejfv), and. Polivy® (polatuzumab vedotin-piiq) are three clinically approved ADCs that contain. After ADC internalization, the released MMAE in the tumor cells can enter surrounding cells and cause bystander killing [3]. This advantage of MMAE leads to an efficient killing of tumor cells.

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