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. 2021 Mar 23;10(6):1332.
doi: 10.3390/jcm10061332.

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

Hsuan Ping Chang  1 , Yuen Kiu Cheung  1 , Dhaval K Shah  1
Affiliations

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

Hsuan Ping Chang et al. J Clin Med. .

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.

Keywords: antibody–drug conjugate (ADC); biodistribution; monomethyl auristatin E (MMAE); physiological-based pharmacokinetic (PBPK) model; tissue pharmacokinetics (PK).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of monomethyl auristatin E (MMAE) physiological-based pharmacokinetic (PBPK) model. (a) Structure of the whole-body PBPK model for MMAE. All tissue compartments are connected in an anatomical manner with blood flow indicated by the solid arrows. (b) Structure of the tissue level PBPK model for MMAE. Each tissue compartment is divided into the vascular, endothelial cell, interstitial, and cellular sub-compartments. The vascular sub-compartment is further divided into plasma and blood cells. For a detailed description of the symbols and drug disposition processes, please refer to the model structure section in the method section. (c) Schematics of the cell-level tumor disposition model for MMAE. For a detailed description of the symbols and drug disposition process, please refer to Table 1 and Model structure section in the Materials and Methods.
Figure 2
Figure 2
Observed whole-body pharmacokinetics (PK) of MMAE in mice after intravenous administration of 0.1 mg/kg MMAE dose. The figure displays the mean (SD) observed concentration (black dots) in plasma, tissues, and tumor. All the PK profiles (truncated to 24 h) are superimposed in the last panel.
Figure 3
Figure 3
Comparison of PBPK model fitted and observed PK profiles of MMAE. The figure displays observed (dots) and model predicted (solid lines) plasma, tissues, and tumor concentration vs. time profiles of MMAE in mice after intravenous administration of 0.1 mg/kg dose.
See this image and copyright information in PMC

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