Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE)
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...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-03-01
|
| Series: | Journal of Clinical Medicine |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2077-0383/10/6/1332 |
| _version_ | 1797540312862687232 |
|---|---|
| author | Hsuan Ping Chang Yuen Kiu Cheung Dhaval K. Shah |
| author_facet | Hsuan Ping Chang Yuen Kiu Cheung Dhaval K. Shah |
| author_sort | Hsuan Ping Chang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T12:58:22Z |
| format | Article |
| id | doaj.art-b6056823fc484c8eb4ce914ba9ec912b |
| institution | Directory Open Access Journal |
| issn | 2077-0383 |
| language | English |
| last_indexed | 2024-03-10T12:58:22Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Clinical Medicine |
| spelling | doaj.art-b6056823fc484c8eb4ce914ba9ec912b2023-11-21T11:43:34ZengMDPI AGJournal of Clinical Medicine2077-03832021-03-01106133210.3390/jcm10061332Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE)Hsuan Ping Chang0Yuen Kiu Cheung1Dhaval K. Shah2Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, USADepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, USADepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, USAMonomethyl 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.https://www.mdpi.com/2077-0383/10/6/1332antibody–drug conjugate (ADC)monomethyl auristatin E (MMAE)biodistributiontissue pharmacokinetics (PK)physiological-based pharmacokinetic (PBPK) model |
| spellingShingle | Hsuan Ping Chang Yuen Kiu Cheung Dhaval K. Shah Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE) Journal of Clinical Medicine antibody–drug conjugate (ADC) monomethyl auristatin E (MMAE) biodistribution tissue pharmacokinetics (PK) physiological-based pharmacokinetic (PBPK) model |
| title | Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE) |
| title_full | Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE) |
| title_fullStr | Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE) |
| title_full_unstemmed | Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE) |
| title_short | Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE) |
| title_sort | whole body pharmacokinetics and physiologically based pharmacokinetic model for monomethyl auristatin e mmae |
| topic | antibody–drug conjugate (ADC) monomethyl auristatin E (MMAE) biodistribution tissue pharmacokinetics (PK) physiological-based pharmacokinetic (PBPK) model |
| url | https://www.mdpi.com/2077-0383/10/6/1332 |
| work_keys_str_mv | AT hsuanpingchang wholebodypharmacokineticsandphysiologicallybasedpharmacokineticmodelformonomethylauristatinemmae AT yuenkiucheung wholebodypharmacokineticsandphysiologicallybasedpharmacokineticmodelformonomethylauristatinemmae AT dhavalkshah wholebodypharmacokineticsandphysiologicallybasedpharmacokineticmodelformonomethylauristatinemmae |